Re-revision and mortality rate following revision total hip arthroplasty for infection.

Aims: This study compares the re-revision rate and mortality following septic and aseptic revision hip arthroplasty (rTHA) in registry data, and compares the outcomes to previously reported data. Methods: This is an observational cohort study using data from the German Arthroplasty Registry (EPRD). A total of 17,842 rTHAs were included, and the rates and cumulative incidence of hip re-revision and mortality following septic and aseptic rTHA were analyzed with seven-year follow-up. The Kaplan-Meier estimates were used to determine the re-revision rate and cumulative probability of mortality following rTHA. Results: The re-revision rate within one year after septic rTHA was 30%, and after seven years was 34%. The cumulative mortality within the first year after septic rTHA was 14%, and within seven years was 40%. After multiple previous hip revisions, the re-revision rate rose to over 40% in septic rTHA. The first six months were identified as the most critical period for the re-revision for septic rTHA. Conclusion: The risk re-revision and reinfection after septic rTHA was almost four times higher, as recorded in the ERPD, when compared to previous meta-analysis. We conclude that it is currently not possible to assume the data from single studies and meta-analysis reflects the outcomes in the 'real world'. Data presented in meta-analyses and from specialist single-centre studies do not reflect the generality of outcomes as recorded in the ERPD. The highest re-revision rates and mortality are seen in the first six months postoperatively. The optimization of perioperative care through the development of a network of high-volume specialist hospitals is likely to lead to improved outcomes for patients undergoing rTHA, especially if associated with infection.

Periacetabular osteotomy for symptomatic hip dysplasia in middle aged patients: does age alone matter?

BACKGROUND: Conflicting evidence exists regarding outcomes in middle-aged patients undergoing periacetabular osteotomy (PAO) for symptomatic developmental dysplasia of the hip (DDH). AIMS: To compare patient reported outcomes (PROMs) of middle-aged PAO patients with younger patient groups. METHODS: Retrospective analysis of prospectively collected data of PAO patients between 01/2015 and 06/2017 at a single orthopedic university center with a primary diagnosis of symptomatic DDH. The cohort was divided into four age groups and compared: < 20, 20-30, 30-40 and > 40 years. Joint function was assessed using iHOT-12, mHHS and SHV. Activity level was assessed using UCLA Activity score. Patient satisfaction and pain were assessed on the numerical rating scale 0-10. Conversion rates to THA were assessed. RESULTS: Out of 202 PAOs, 120 cases with complete data were included. Mean follow-up was 63 months (range 47-81 months). Eighteen patients were < 20 years old, 54 were 20-30 years, 37 were 30-40 years, 11 patients were older than 40. No significant differences were observed for preoperative or postoperative iHOT-12 (p = 0.898; p = 0.087), mHHS (p = 0.878; p = 0.103), SHV (p = 0.602; p = 0.352) or UCLA (p = 0.539; p = 0.978) between groups. Improvement deltas were also not significantly different for all PROMs. Postoperative patient satisfaction was similar between groups (p = 0.783). CONCLUSION: Patients with symptomatic DDH may benefit from PAO even at middle age with similar outcomes and pre- to postoperative improvements as younger age groups. Indication should be based on biological age and preoperative joint condition rather than age.

The influence of lumbo-sacral transitional vertebrae in developmental dysplasia of the hip: a matched pair analysis.

Lumbo-sacral transitional vertebrae (LSTV) are the most common congenital alteration of the lumbo-sacral junction and known to significantly influence pelvic anatomy. However, the influence of LSTV on dysplasia of the hip (DDH) and the surgical treatment by periacetabular osteotomy (PAO) remains unknown. We retrospectively examined standardized standing anterior-posterior pelvic radiographs of 170 patients in 185 PAO procedures. Radiographs were examined for LSTV, lateral-central-edge-angle (LCEA), Tönnis-angle (TA), femoral-head-extrusion index (FHEI), and anterior-wall-index (AWI) and posterior-wall-index (PWI). Patients with LSTV were compared to an age- and sex-matched control group. Patient-reported outcome measurements (PROMs) were evaluated pre- and in the mean 63.0 months (range 47-81 months) postoperatively. 43 patients (25.3%) had LSTV. Patients with LSTV had significantly greater PWI (p = 0.025) compared to the matched control group. No significant differences were seen in AWI (p = 0.374), LCEA (p = 0.664), TA (p = 0.667), and FHEI (p = 0.886). Between the two groups, no significant differences were detected in pre- or postoperative PROMs. Due to the increased dorsal femoral head coverage in patients with LSTV and DDH compared to patients with sole DDH, a more pronounced ventral tilting might be performed in those patients with prominent posterior wall sign to avoid anterior undercoverage, which is a significant predictor for premature conversion to hip arthroplasty after PAO. However, anterior overcoverage or acetabular retroversion must be avoided due to the risk of femoroacetabular impingement. Patients with LSTV reported similar functional outcomes and activity after PAO as the control group. Therefore, even for patients with concomitant LSTV, which are frequent with one-fourth in our cohort, PAO is an efficient treatment option to improve clinical symptoms caused by DDH.

Avoiding Spinal Implant Failures in Osteoporotic Patients: A Narrative Review.

STUDY DESIGN: Narrative review. OBJECTIVES: With an aging population, the prevalence of osteoporosis is continuously rising. As osseous integrity is crucial for bony fusion and implant stability, previous studies have shown osteoporosis to be associated with an increased risk for implant failure and higher reoperation rates after spine surgery. Thus, our review's purpose was to provide an update of evidence-based solutions in the surgical treatment of osteoporosis patients. METHODS: We summarize the existing literature regarding changes associated with decreased bone mineral density (BMD) and resulting biomechanical implications for the spine as well as multidisciplinary treatment strategies to avoid implant failures in osteoporotic patients. RESULTS: Osteoporosis is caused by an uncoupling of the bone remodeling cycle based on an unbalancing of bone resorption and formation and resulting reduced BMD. The reduction in trabecular structure, increased porosity of cancellous bone and decreased cross-linking between trabeculae cause a higher risk of complications after spinal implant-based surgeries. Thus, patients with osteoporosis require special planning considerations, including adequate preoperative evaluation and optimization. Surgical strategies aim towards maximizing screw pull-out strength, toggle resistance, as well as primary and secondary construct stability. CONCLUSIONS: As osteoporosis plays a crucial role in the fate of patients undergoing spine surgery, surgeons need to be aware of the specific implications of low BMD. While there still is no consensus on the best course of treatment, multidisciplinary preoperative assessment and adherence to specific surgical principles help reduce the rate of implant-related complications.

Approach-related anatomical differences in patients with lumbo-sacral transitional vertebrae undergoing lumbar fusion surgery at level L4/5.

INTRODUCTION: Lumbo-sacral transitional vertebrae (LSTV) are accompanied by changes in soft tissue anatomy. The aim of our retrospective study was to evaluate the effects of LSTV as well as the number of free lumbar vertebrae on surgical approaches of ALIF, OLIF and LLIF at level L4/5. MATERIAL AND METHODS: We assessed the CTs of 819 patients. Of these, 53 had LSTV from which 11 had six (6LV) and 9 four free lumbar vertebrae (4LV). We matched them for sex and age to a control group. RESULTS: Patients with LSTV had a higher iliac crest and vena cava bifurcation, a greater distance between the common iliac veins and an anterior translation of the psoas muscle at level L4/5. In contrast, patients with 6LV had a lower iliac crest and aortic bifurcation, no differences in vena cava bifurcation and distance between the iliac veins compared to the control group. CONCLUSIONS: For patients with LSTV and five or four free lumbar vertebrae, the LLIF approach at L4/5 may be hindered due to a high riding iliac crest as well as anterior shift of the psoas muscle. Whereas less mobilization and retraction of the iliac veins may reduce the risk of vascular injury at this segment by ALIF and OLIF. For patients with 6LV, a lower relative height of the iliac crest facilitates lateral approach during LLIF. For ALIF and OLIF, a stronger vessel retraction due to the deeper-seated vascular bifurcation is necessary during ALIF and is therefore potentially at higher risk for vascular injury.

Safe Zones for Spinopelvic Screws in Patients With Lumbosacral Transitional Vertebra.

STUDY DESIGN: Retrospective matched-pair analysis. OBJECTIVES: Lumbosacral transitional vertebrae (LSTV) have a reported prevalence of 4-36% in the population. The safe zones for screw placement for spinopelvic fusion in adult spinal deformity surgery for patients with LSTV have not been described in the literature. Our study aimed to assess the safety of S1-pedicle screw (S1PS), S2-alar screw (S2AS), S2-alar-iliac screw (S2AIS), and iliac screw (IS) placement in patients with LSTV. METHODS: Out of the 819 examined patients, 49 patients with LSTV were included in our retrospective analysis with a matched pair control group. We used the 3-dimensional planning tool mediCAD for screw placement of S1PS, S2AS, S2AIS, IS with different angles, length and diameters. RESULTS: We evaluated a total of 10 192 screw trajectories. No serious complications occurred due to the trajectories used for S1PS. LSTV increased the risk of vessel injury for S2AS trajectories (P = .001) but not for S2AIS (P = .526). Besides the presence of an LSTV, the screw trajectory had a major influence on the frequency of serious complications. CONCLUSIONS: Sacral anchoring of long spinal constructions using S1PS, S2AS, S2AIS and IS is also possible in the presence of LSTV. For S2AS the trajectory with 30° lateral and caudal angulation of 10° showed the least vascular injuries and the least sacro-iliac-joint violations in patients with LSTV. S2AIS trajectories with 40° lateral and 0° sagittal angulation reduced the risk of serious complications in our patients collective with LSTV.

Validation of the TLICS and AOSpine injury score for surgical management of paediatric traumatic spinal injuries.

INTRODUCTION: Fractures of the thoracolumbar spine in children are rare. Consequently, classification systems providing detailed treatment recommendations as already established in adults are still lacking in the paediatric population. We aimed to evaluate the validity and reliability of the thoracolumbar injury classification and severity score system (TLICS) and the AOSpine injury score in paediatric patients presenting with a traumatic fracture of the thoracolumbar spine. MATERIALS AND METHODS: Patients younger than 18 years presenting with a traumatic thoracolumbar fracture at a large academic trauma centre between 2010 and 2020 were included retrospectively. Demographic and clinical data were retrieved from electronic medical reports. The AOSpine injury score and TLICS were calculated using plain radiography, magnetic resonance imaging, and/or computed tomography. RESULTS: Sixty patients with 167 fractures were included. Surgical treatment was performed in 14 patients. The mean AOSpine injury score was 1.49 ± 2.0, the mean TLICS was 1.32 ± 1.65. A significant correlation between the classification systems was found (Spearman r = 0.975, p < 0.001). Interrater reliability analysis revealed Kappa values of 0.868 for the TLICS and 0.860 for the AOSpine injury score (p < 0.001). Contingency table analysis showed a sensitivity of 1.00 and specificity of 0.94 for the AOSpine injury score and a sensitivity of 0.90 and specificity of 0.90 for the TLICS in predicting the performed treatment. CONCLUSIONS: Our results confirm that the TLICS is a valid classification system for determining treatment decisions in paediatric patients and show slightly higher accuracy of the AOSpine injury score as well as high interrater reliabilities for both classification systems.

Two-stage revision for periprosthetic joint infection in cemented total hip arthroplasty: an increased risk for failure?

BACKGROUND: The impact of the prior fixation mode on the treatment outcome of chronic periprosthetic joint infection (PJI) of the hip is unclear. Removal of cemented total hip arthroplasty (THA) is particularly challenging and residual cement might be associated with reinfection. This study seeks to compare the results of two-stage revision for PJI in cemented and cementless THA. METHODS: We reviewed 143 consecutive patients undergoing two-stage revision THA for PJI between 2013 and 2018. Thirty-six patients with a fully cemented (n = 6), hybrid femur (n = 26) or hybrid acetabulum (n = 4) THA (cemented group) were matched 1:2 with a cohort of 72 patients who underwent removal of a cementless THA (cementless group). Groups were matched by sex, age, number of prior surgeries and history of infection treatment. Outcomes included microbiological results, interim re-debridement, reinfection, all-cause revision, and modified Harris hip scores (mHHS). Minimum follow-up was 2 years. RESULTS: Compared with PJI in cementless THA, patients undergoing removal of cemented THA had increasingly severe femoral bone loss (p = 0.004). Patients in the cemented group had an increased risk for positive cultures during second-stage reimplantation (22% compared to 8%, p = 0.043), higher rates of reinfection (22% compared to 7%, p = 0.021) and all-cause revision (31% compared to 14%, p = 0.039) compared to patients undergoing two-stage revision of cementless THA. Periprosthetic femoral fractures were more frequent in the group of patients with prior cementation (p = .004). Mean mHHS had been 37.5 in the cemented group and 39.1 in the cementless group, and these scores improved significantly in both groups (p < 0.01). CONCLUSION: This study shows that chronic infection in cemented THA might be associated with increased bone loss, higher rates of reinfection and all-cause revision following two-stage revision. This should be useful to clinicians counselling patients with hip PJI and can guide treatment and estimated outcomes.

Comparison of three validated systems to analyse spinal shape and motion.

The assessment of spinal shape and mobility is of great importance for long-term therapy evaluation. As frequent radiation should be avoided, especially in children, non-invasive measurements have gained increasing importance. Their comparability between each other however stays elusive. Three non-invasive measurement tools have been compared to each other: Idiag M360, raster stereography and Epionics SPINE. 30 volunteers (15 females/15 males) have each been assessed by each system, investigating lumbar lordosis, thoracic kyphosis and spinal range-of-motion in the sagittal plane. Lumbar lordosis differed significantly (p < 0.001) between measurement devices but correlated significant to each other (Pearson's r 0.5-0.6). Regarding thoracic kyphosis no significant difference and a high correlation (r = 0.8) could be shown between Idiag M360 and raster stereography. For lumbar mobility resulting measurements differed significantly and correlated only moderate between Idiag M360 and Epionics SPINE. Although the different measurement systems are moderate to high correlated to each other, their absolute agreement is limited. This might be explained by differences in their angle definition for lordotic and kyphotic angle, their measurement placement, or their capturing of mobility (static vs. dynamic assessment). Therefore, for long-term evaluation of the back profile, inter-modal comparison of values between different non-invasive devices should be avoided.

Gas within the Intervertebral Disc Does Not Rule Out Spinal Infection-A Case Series of 135 Patients with Spontaneous Spondylodiscitis.

Gas in the intervertebral disc is mainly associated with degenerative disc diseases and experts generally assume that it is unlikely in spinal infection. However, large-scale studies supporting this notion are lacking, which is why our study's aim was to analyze the prevalence of and factors associated with the occurrence of gas in patients with spontaneous spondylodiscitis. Patients presenting with spontaneous spondylodiscitis from 2006 to 2020 were included retrospectively. Exclusion criteria were previous interventions in the same spinal segment and missing imaging data. Clinical data were retrieved from electronic medical reports. Computed tomography (CT) scans were evaluated for the presence of intervertebral gas. Causative pathogens were identified from CT-guided biopsy, open biopsy, intraoperative tissue samples, and/or blood cultures. 135 patients with a mean age of 66.0 ± 13.7 years were included. In 93 patients (68.9%), a causative pathogen was found. Intervertebral gas was found in 31 patients (23.0%) in total and in 19 patients (20.4%) with positive microbiology. Patients with gas presented with significantly higher body temperatures (37.2 ± 1.1 vs. 36.8 ± 0.7 °C, p = 0.044) and CRP levels (134.2 ± 127.1 vs. 89.8 ± 97.3 mg/L, p = 0.040) on admission. As a considerable number of patients with spondylodiscitis showed intervertebral gas formation, the detection of intervertebral gas is not suited to ruling out spondylodiscitis but must be interpreted in the context of other imaging and clinical findings, especially in elderly patients.

Spinopelvic mobility is influenced by pre-existing contralateral hip arthroplasty: a matched-pair analysis in patients undergoing hip replacement.

BACKGROUND: Spinopelvic mobility gained increased attention as a contributing factor for total hip arthroplasty (THA) instability. However, it is unknown how a pre-existing THA affects spinopelvic mobility. Therefore, a propensity-score-matched analysis of primary THA patients comparing the individual segments of spinopelvic mobility between patients with pre-existing THA and no-existing THA was conducted. Consequently, the study aimed to discuss (1) whether patients with a pre-existing THA have altered spinopelvic mobility compared to the control group and (2) if spinopelvic mobility changes after THA. METHODS: A prospective observational study enrolled 197 elective primary THA patients, including N = 44 patients with a pre-existing unilateral THA. Using propensity-score matching adapted for age, sex, and BMI, N = 44 patients without a pre-existing THA were determined. The patients received stereoradiography in standing and relaxed sitting position pre- and postoperatively. Assessed parameters were lumbar lordosis (LL), pelvic tilt (PT), and pelvic femoral angle (PFA). Key parameters of the spinopelvic mobility were defined as lumbar flexibility (∆LL = LLstanding - LLsitting), pelvic mobility (∆PT = PTstanding - PTsitting) and hip motion (∆PFA = PFAstanding - PFAsitting). Pelvic mobility was classified as stiff (∆PT < 10°), normal (∆PT ≥ 10°-30°) and hypermobile (∆PT > 30°). The Wilcoxon rank sum test for dependent samples was used. RESULTS: Pelvic mobility was significantly increased in the pre-existing THA group (∆PT 18.2° ± 10.7) compared to the control group (∆PT 7.7° ± 8.0; p < 0.001) preoperatively and postoperatively (pre-existing: 22.2° ± 9.3; control: 17.0° ± 9.2, p = 0.022). Lumbar flexibility was significantly increased in the pre-existing THA group (∆LL 21.6° ± 11.8) compared to the control group (∆LL 12.4° ± 7.8; p < 0.001) preoperatively and postoperatively (pre-existing: 25.7° ± 11.0; control: 19.0° ± 10.2; p = 0.011). The contribution of stiff pelvic mobility is distinctly smaller in the pre-existing THA group (25%) than in the control group (75%) preoperatively. CONCLUSIONS: Pre-existing THA is associated with significantly enhanced pelvic mobility and lumbar flexibility. Accordingly, we identified the patients without a pre-existing THA as risk candidates with higher likelihood for pathological spinopelvic mobility. This information will assist arthroplasty surgeons in deciding which THA candidates require preoperative radiological screening for pathologic spinopelvic mobility. LEVEL OF EVIDENCE: Level II prospective cohort study.

Does obesity affect acetabular cup position, spinopelvic function and sagittal spinal alignment? A prospective investigation with standing and sitting assessment of primary hip arthroplasty patients.

BACKGROUND: Total hip arthroplasty (THA) instability is influenced by acetabular component positioning, spinopelvic function and sagittal spinal alignment. Obesity is considered as a risk factor of THA instability, but the causal relationship remains unknown. This study aimed to investigate the influence of BMI on (1) spinopelvic function (lumbar flexibility, pelvic mobility and hip motion), (2) sagittal spinal alignment pre- and postoperatively and (3) acetabular cup position postoperatively in primary THA patients in a prospective setting. METHODS: One hundred ninety patients receiving primary total hip arthroplasty were enrolled in a prospective cohort study and retrospectively analysed. All patients received stereoradiography (EOS) in standing and relaxed sitting position pre-and postoperatively. C7-sagittal vertical axis (C7-SVA), lumbar lordosis (LL), pelvic incidence (PI), pelvic tilt (PT), anterior plane pelvic tilt (APPT), and pelvic femoral angle (PFA) were assessed. Key parameters of the spinopelvic function were defined as lumbar flexibility (∆ LL = LLstanding - LLsitting), pelvic mobility (∆ PT = PTstanding - PTsitting) and hip motion (∆ PFA = PFAstanding - PFAsitting). Pelvic mobility was further defined based on ∆ PT as stiff, normal and hypermobile (∆ PT < 10°; 10°-30°; > 30°). The patients were stratified to BMI according to WHO definition: normal BMI ≥ 18.5-24.9 kg/m2 (n = 68), overweight ≥ 25.0-29.9 kg/m2 (n = 81) and obese ≥ 30-39.9 kg/m2 (n = 41). Post-hoc analysis according to Hochberg's GT2 was applied to determine differences between BMI groups. RESULTS: Standing cup inclination was significant higher in the obese group compared to the normal BMI group (45.3° vs. 40.1°; p = 0.015) whereas standing cup anteversion was significantly decreased (22.0° vs. 25.3°; p = 0.011). There were no significant differences for spinopelvic function key parameter lumbar flexibility (∆ LL), pelvic mobility (∆ PT) and hip motion (∆ PFA) in relation to BMI stratified groups. The obese group demonstrated significant enhanced pelvic retroversion compared to the normal BMI group (APPT - 1.8° vs. 2.4°; p = 0.028). The preoperative proportion of stiff pelvic mobility was decreased in the obese group (12.2%) compared to normal (25.0%) and overweight (27.2%) groups. Spinal sagittal alignment in C7-SVA and PI-LL mismatch demonstrated significantly greater imbalance in the obese group compared to the normal BMI group (68.6 mm vs. 42.6 mm, p = 0.002 and 7.7° vs. 1.2°, p = 0.032, respectively) The proportion of patients with imbalanced C7-SVA was higher in the obese (58.5%) than in the normal BMI group (44.1%). CONCLUSIONS: The significantly increased spinal sagittal imbalance with altered pelvic mechanics is a potential cause for the reported increased risk of THA dislocations in obese patients. Consequently, the increased spinal sagittal imbalance in combination with normal pelvic mobility need to be taken into account when performing THA in obese patients.

Outcomes Following ABO-Incompatible Kidney Transplantation Performed After Desensitization by Nonantigen-Specific Immunoadsorption.

BACKGROUND: For desensitization of ABO-incompatible kidney transplant recipients we recently proposed nonantigen-specific immunoadsorption (IA) and rituximab. METHODS: We now compared clinical outcomes of 34 ABO-incompatible living-donor kidney recipients who were transplanted using this protocol with that of 68 matched ABO-compatible patients. In addition, we analyzed efficacy and cost of nonantigen-specific as compared to blood group antigen-specific IA. RESULTS: Before desensitization, the median isoagglutinin titer of 34 ABO-incompatible patients was 1:64 (Coombs technique). Patients received a median of 7 preoperative IA treatments. Twenty-four patients had a median of 2 additional plasmapheresis treatments to reach the preoperative target isoagglutinin titer of 1:8 or less. After a median postoperative follow-up of 22 months, overall graft survival in the ABO-incompatible group was not significantly different from that in ABO-compatible patients (log-rank P = 0.20), whereas patient survival tended to be lower (log-rank P = 0.05). The incidence of rejection episodes was 15% in both groups. The ABO-incompatible kidney recipients had a higher incidence of BK virus replication (P = 0.04) and nephropathy (P = 0.01) and showed more often colonization with multidrug resistant bacteria (P = 0.02). In comparison to blood group antigen-specific IA, nonantigen-specific IA showed equal efficacy but was associated with reduction in cost. CONCLUSIONS: Clinical outcomes of ABO-incompatible patients desensitized with a nonantigen-specific IA device and rituximab do not differ from that of matched ABO-compatible patients although a trend toward reduced patient survival was noted. Special attention must be paid to the higher incidence of BK virus infection in recipients of ABO-incompatible grafts.

Evolution of allograft fibrosis and function in kidney transplant recipients: a retrospective analysis of stable patients under CNI and mTORi.

Histological evaluations of renal allograft biopsies are essential for diagnosis, but still show a low predictive value for long-term allograft function. One limitation relies on the fact that the analysis is usually based on a single biopsy sample, and therefore, no dynamic changes are considered. Using two distinct approaches, we evaluated the evolution of fibrosis and related markers in 36 stable kidney transplant patients under calcineurin inhibitor therapy with two indication biopsies each, prior and at least 6 months after substitution by mTORi (N = 18), or maintenance on CNI (N = 18). In the method comparison, both Banff chronicity score and the digitally assessed fibrosis were correlated with allograft function at biopsy (r = -0.36 and r = -0.72, P = 0.002 and P < 0.0001, respectively). However, only the progression of fibrosis digitally assessed was correlated with allograft function loss, not only within the time between biopsies (r = -0.47, P = 0.004) but also in the 60-month follow-up (r = -0.47, P = 0.006). In the group analysis, despite of a higher incidence of C4d positivity (P = 0.05), progression of fibrosis, TGF-ß1 expression, and allograft function decline were significantly lower after conversion to mTORi compared with maintenance on CNI (P = 0.05, P = 0.02 and P = 0.01, respectively). PDGF, VEGF, b-FGF, and HIF1A expressions remained stable over time regardless of therapy.

Generation of suppressive blood cells for control of allograft rejection.

Our previous studies in rats showed that incubation of monocytic dendritic cells (DCs) with the chemotherapeutic drug mitomycin C (MMC) renders the cells immunosuppressive. Donor-derived MMC-DCs injected into the recipient prior to transplantation prolonged heart allograft survival. Although the generation of DCs is labour-intensive and time-consuming, peripheral blood mononuclear cells (PBMCs) can be easily harvested. In the present study, we analyse under which conditions DCs can be replaced by PBMCs and examine their mode of action. When injected into rats, MMC-incubated donor PBMCs (MICs) strongly prolonged heart allograft survival. Removal of monocytes from PBMCs completely abrogated their suppressive effect, indicating that monocytes are the active cell population. Suppression of rejection was donor-specific. The injected MICs migrated into peripheral lymphoid organs and led to an increased number of regulatory T-cells (Tregs) expressing cluster of differentiation (CD) markers CD4 and CD25 and forkhead box protein 3 (FoxP3). Tolerance could be transferred to syngeneic recipients with blood or spleen cells. Depletion of Tregs from tolerogenic cells abrogated their suppressive effect, arguing for mediation of immunosuppression by CD4⁺CD25⁺FoxP3⁺ Tregs. Donor-derived MICs also prolonged kidney allograft survival in pigs. MICs generated from donor monocytes were applied for the first time in humans in a patient suffering from therapy-resistant rejection of a haploidentical stem cell transplant. We describe, in the present paper, a simple method for in vitro generation of suppressor blood cells for potential use in clinical organ transplantation. Although the case report does not allow us to draw any conclusion about their therapeutic effectiveness, it shows that MICs can be easily generated and applied in humans.

The extent of HLA-DR expression on HLA-DR(+) Tregs allows the identification of patients with clinically relevant borderline rejection.

Regulatory T cells (Tregs) were shown to be involved into the pathogenesis of acute rejection after transplantation. The suppressive activity of the total regulatory T cell pool depends on its percentage of highly suppressive HLA-DR(+) -Treg cells. Therefore, both the suppressive activity of the total Treg pool and the extent of HLA-DR expression of HLA-DR(+) -Tregs (MFI HLA-DR) were estimated in non transplanted volunteers, patients with end-stage renal failure (ESRF), healthy renal transplant patients with suspicion on rejection, due to sole histological Bord-R or sole acute renal failure (ARF), and patients with clinically relevant borderline rejection (Bord-R and ARF). Compared to patients with only Bord-R or only ARF, the suppressive activity of the total Treg cell pool was exclusively reduced in patients with clinically relevant Bord-R. In parallel, the HLA-DR MFI of the DR(+) -Treg subset was significantly decreased in these patients, due to a significantly lower proportion of DR(high+) -Tregs, which were shown to have the highest suppressive capacity within the total Treg pool. Our findings clearly demonstrate that the determination of the HLA-DR MFI of the HLA-DR(+) -Treg subset allows a highly sensitive, specific and non-invasive discrimination between patients with clinically relevant Bord-R (Bord and ARF) and patients with subclinical rejection or other causes of transplant failure.

Cellular infiltrates and NFκB subunit c-Rel signaling in kidney allografts of patients with clinical operational tolerance.

BACKGROUND: Nuclear factor kappa B (NFκB) plays a potential role in tolerance by orchestrating onset and resolution of inflammation and regulatory T cell differentiation through subunit c-Rel. We characterized cellular infiltrates and expression of NFκB1, c-Rel and its upstream regulators phosphatidylinositol 3-kinase/RAC-alpha serine/threonine kinase, in allograft biopsies from patients with spontaneous clinical operational tolerance (COT). METHODS: Paraffin-fixed kidney allograft biopsies from 40 patients with COT (n=4), interstitial rejection (IR; n=12), borderline changes (BC; n=12), and long-term allograft function without rejection (NR; n=12) were used in the study. Cellular infiltrates and immunohistochemical expression of key proteins of the NFκB pathway were evaluated in the cortical tubulointerstitium and in cellular infiltrates using digital image analysis software. Results were given as mean±SEM. RESULTS: Biopsies from patients with COT exhibited a comparable amount of cellular infiltrate to IR, BC, and NR (COT, 191±81; IR, 291±62; BC, 178±45; and NR, 210±42 cells/mm) but a significantly higher proportion of forkhead box P3-positive cells (COT, 11%±1.7%; IR, 3.5%±0.70%; BC, 3.4%±0.57%; and NR, 3.7%±0.78% of infiltrating cells; P=0.02). c-Rel expression in cellular infiltrates was significantly elevated in IR, BC, and NR when analyzing the number of positive cells per mm (P=0.02) and positive cells per infiltrating cells (P=0.04). In contrast, tubular PI3K and c-Rel expression were significantly higher in IR and BC but not in NR compared with COT (P=0.03 and P=0.006, respectively). With RAC-alpha serine-threonine kinase, similar tendencies were observed (P=0.2). CONCLUSIONS: Allografts from COT patients show significant cellular infiltrates but a distinct expression of proteins involved in the NFκB pathway and a higher proportion of forkhead box P3-positive cells.

Both high and low maternal salt intake in pregnancy alter kidney development in the offspring.

In humans, low glomerular numbers are related to hypertension, cardiovascular, and renal disease in adult life. The present study was designed 1) to explore whether above- or below-normal dietary salt intake during pregnancy influences nephron number and blood pressure in the offspring and 2) to identify potential mechanisms in kidney development modified by maternal sodium intake. Sprague-Dawley rats were fed low (0.07%)-, intermediate (0.51%)-, or high (3.0%)-sodium diets during pregnancy and lactation. The offspring were weaned at 4 wk and subsequently kept on a 0.51% sodium diet. The kidney structure was assessed at postnatal weeks 1 and 12 and the expression of proteins of interest at term and at week 1. Blood pressure was measured in male offspring by telemetry from postnatal month 2 to postnatal month 9. The numbers of glomeruli at weeks 1 and 12 were significantly lower and, in males, telemetrically measured mean arterial blood pressure after month 5 was higher in offspring of dams on a high- or low- compared with intermediate-sodium diet. A high-salt diet was paralleled by higher concentrations of marinobufagenin in the amniotic fluid and an increase in the expression of both sprouty-1 and glial cell-derived neutrophic factor in the offspring's kidney. The expression of FGF-10 was lower in offspring of dams on a low-sodium diet, and the expression of Pax-2 and FGF-2 was lower in offspring of dams on a high-sodium diet. Both excessively high and excessively low sodium intakes during pregnancy modify protein expression in offspring kidneys and reduce the final number of glomeruli, predisposing the risk of hypertension later in life.

Effect of paricalcitol and calcitriol on aortic wall remodeling in uninephrectomized ApoE knockout mice.

Despite an only minor reduction in the glomerular filtration rate, uninephrectomy (UNX) markedly accelerates the rate of growth of atherosclerotic plaques in ApoE-/- mice. It has been suggested that vitamin D receptor (VDR) activation exerts an antiproliferative effect on vascular smooth muscle cells, but the side effects may limit its use. To assess a potentially different spectrum of actions, we compared the effects of paricalcitol and calcitriol on remodeling and calcification of the aortic wall in sham-operated and UNX ApoE-/- mice on a diet with normal cholesterol content. Sham-operated and UNX mice were randomly allotted to treatment with solvent, calcitriol (0.03 µg/kg) or paricalcitol (0.1 µg/kg) 5 times/wk intraperitoneally for 10 wk. Semithin (0.6 µm) sections of the aorta were analyzed by 1) morphometry, 2) immunohistochemistry, and 3) Western blotting of key proteins involved in vascular calcification and growth. Compared with sham-operated animals (5.6 ± 0.24), the wall-to-lumen ratio (x100) of the aorta was significantly higher in solvent- and calcitriol-treated UNX animals (6.64 ± 0.27 and 7.17 ± 0.81, respectively, P < 0.05), but not in paricalcitol-treated UNX (6.1 5 ± 0.32). Similar differences were seen with respect to maximal plaque height. Expression of transforming growth factor (TGF)-ß1 in aortic intima/plaque was also significantly higher in UNX solvent and UNX calcitriol compared with sham-operated and UNX paricalcitol animals. Treatment with both paricalcitol and calcitriol caused significant elevation of VDR expression in the aorta. While at the dose employed paricalcitol significantly reduced TGF-ß expression in plaques, calcitriol in contrast caused significant vascular calcification and elevated expression of related proteins (BMP2, RANKL, and Runx2).

In renal transplants with delayed graft function chemokines and chemokine receptor expression predict long-term allograft function.

BACKGROUND: Chronic loss of renal allograft function is associated with interstitial fibrosis and tubular atrophy (IF/TA). Independent of the underlying reason, one initial step in the development of fibrosis is chemokine-driven invasion of leukocytes from the blood vessels into the allograft. We studied the role of chemokines in kidney allografts with delayed graft function and the subsequent long-term outcome of renal function and fibrosis. METHODS: We examined repetitive biopsies of 30 patients without signs of acute rejection but with initially delayed graft function for IF/TA. In addition, we examined the expression of chemokine receptor (CCR)-1 and CCR2 on invaded leukocytes and macrophages and the corresponding ligands regulated upon activation, normal t-cell expressed, and secreted (RANTES) and monocyte chemotactic protein-1 on residential kidney cells. RESULTS: The initial expression of CCR1 positive invading cells and RANTES in glomerular cells correlated with the allograft function 12 months after transplantation and at last follow-up. The expression was independent of donor characteristics such as age, gender, infectious state, cause of death, or use of vasopressive agents. Furthermore, it did not correlate with the duration of cold ischemia time. Among the patients with the most progressive loss of allograft function follow-up biopsy specimen did not reveal any signs of rejection but showed increased CCR1 and RANTES expression in the interstitium suggesting ongoing inflammation and fibrosis. CONCLUSION: An early expression of RANTES in renal allografts with delayed graft function with consecutive invasion of CCR1 positive cells seems to promote ongoing IF/TA and to worse renal allograft outcome.