Effects of immediate switch from cyclosporine microemulsion to tacrolimus at first acute rejection in renal allograft recipients

BACKGROUND: A number of institutions have reported favorable results in renal transplant patients after conversion from cyclosporine (CsA) to tacrolimus at the time of acute rejection, but no prospective, controlled study has been performed to date. Here, we report the first randomized study comparing patients whose therapy was changed at a first episode of acute rejection to tacrolimus with those who were maintained on CsA microemulsion (ME). METHODS: This 3-month, prospective, open, multicenter, parallel-group study was conducted at 15 centers in seven European countries. In total, 119 renal graft recipients experiencing a first biopsy-proven acute rejection episode while receiving CsA-ME were randomized (1:1) to start tacrolimus-based therapy (n=61) or to continue CsA-ME-based therapy (n=58). RESULTS: Baseline characteristics were comparable for both groups. The initial rejection episode responded to steroid treatment in 93.4% (tacrolimus) and 63.8% (CsA-ME) (P=0.001), respectively. In patients at risk, the incidence of recurrent rejection events within 3 months was significantly lower with tacrolimus therapy (5/57, 8.8%) compared with CsA-ME therapy (15/44, 34.1%) (P=0.002). Patient and graft survival were similar in both study groups 3 months after randomization. The most frequently reported adverse events were increased serum creatinine (29.5% vs. 22.4%), hypertension (24.6% vs. 22.4%), and urinary tract infection (18.0% vs. 20.7%) for tacrolimus versus CsA-ME. Tremor was more common in tacrolimus treated-patients (17.4% vs. 2.1%, P=0.011). CONCLUSIONS: Early conversion to tacrolimus therapy benefited the resolution of acute rejection episodes and significantly reduced the risk of recurrent rejection compared with continuation of CsA-ME.     

Clinical and structural results of partial supraspinatus tears treated by subacromial decompression without repair

Patients with primary impingement and articular sided partial tears of the supraspinatus are often treated by subacromial decompression without repair, if the extent of the tear is estimated to be below 50% of tendon thickness. It has been questioned whether repair of these cuff lesions is necessary, because these tears could progress to full thickness tears with deteriorating clinical results. Our hypothesis was that subacromial decompression without repair of the supraspinatus tendon leads to significant clinical improvement for patients with grade I and II articular sided tears without progression to a full thickness tear on a regular basis. 46 consecutive patients (av. Age 59.2 years, range 33–76.6 years) were retrospectively reviewed after an average follow up of 50.3 months (36–86 months). 26 patients (43.5%) had a grade I tear according to Ellman, which was left alone, 20 patients suffered from a grade II tear, which was debrided. Clinical outcome was assessed with the ASES Score and ultrasound evaluation was performed on all patients to detect possible progression to a full thickness tear. The average ASES Score significantly improved from 37.4 to 86.6 points (p < 0.0001). The mean postoperative Constant Score was 87.6 points. Only three patients (6.5%) progressed to a full thickness tear detectable on ultrasound examination. Only one of these patients had a poor result with an ASES Score of 35 points, the other two were very satisfied and had an ASES score above 90 points. 8 patients showed no more signs of partial tearing on ultrasound and these patients had an average ASES Score of 93.1 points. Overall clinical outcome was rated excellent in 35 cases (76.1%), good in 5 (10.9%), average in 2 (4.3%) and poor in 4 (8.7%). Our results indicate that good and excellent results can be achieved mid- to long term by acromioplasty without repair of the rotator cuff in articular sided partial tears grade I and II. These results reach almost 95% of the value of a healthy shoulder. A better result on ultrasound examination was associated with a superior clinical outcome, while progression to a full thickness tear was rare.     

Modeling changes in intervertebral disc mechanics with degeneration

Mechanical response of the spine to various dynamic loading conditions can be analyzed by way of in vitro and in vivo studies. Ethical concerns, interpretation of conclusions reached in animal studies, and lack of detailed stress distributions in the disc components are the major disadvantages of relying solely on in vivo studies. Intraspecimen variability, difficulty in including muscle activity, and inability to mimic fluid exchange into the disc during unloading are some of the disadvantages of in vitro models. The poroelastic finite element models can provide a method of understanding the relationship between biomechanical performance of the disc due to cyclic loading and disc degeneration. A poroelastic finite element model, including regional variation of strain-dependent permeability and osmotic pressure, was used to study the effect of disc degeneration on biomechanical properties as well as propagation of failure in the disc components when cyclic loading was applied to the lumbar disc. The results predicted that healthy discs were much more flexible than degenerated discs, and the disc stiffness decreased with increasing the number of load cycles independent of degenerative condition. Failure was found to progress as the drained elastic properties of the disc components decreased due to the presence of failure. Poroelastic finite element modeling, including strain-dependent permeability and osmotic pressure, is the most advanced analytical tool currently available that can be used to understand how cyclic loading affects the biomechanical characteristics of a degenerated lumbar disc. However, a complete understanding of behavior of the intervertebral disc will ultimately be achieved only with use of a combination of computational models together with in vitro and in vivo experimental methods. Finite element models of discs with varying degrees of disc degeneration will help clinicians understand the initiation and progression of disc failure and degeneration and will assist in the development of approaches to stimulate the regeneration of disc tissues.     

Still a reasonable goal: Targeting cholesterol in dialysis and advanced chronic kidney disease patients

Chronic kidney disease (CKD) patients have a high burden of cardiovascular disease. In the general population, lipid metabolism disorders, which cause the initiation and progression of atherosclerotic vascular changes, are major targets for preventive and therapeutic strategies in cardiovascular medicine. However, data from large cohort studies and from clinical trials suggest that the treatment guidelines on cardiovascular disease prevention and therapy cannot uncritically be transferred from individuals with intact renal function to CKD patients. Thus, unlike in the general population, neither plasma levels of HDL‐cholesterol, nor the key parameter of HDL‐cholesterol function—that is, cholesterol efflux capacity—predicts future cardiovascular events. Therefore, HDL‐cholesterol should presently not be considered as therapeutic target in CKD patients. In contrast, lowering of LDL‐cholesterol has been shown to reduce cardiovascular events at least among nondialysis CKD patients. The cardiovascular benefit of targeting LDL‐cholesterol among dialysis CKD patients is less evident. We strongly believe that at least some subgroups of dialysis patients may profit from such treatment, particularly those with highest baseline LDL‐cholesterol. Finally, as CKD patients have been characterized to have rather high intestinal cholesterol absorption, and relatively low hepatic cholesterol synthesis, substituting combined statin/ezetimibe treatment for statin monotherapy may be of particular benefit for nephrologic patients.     

Mortality, complications and loss of pulmonary function after pneumonectomy vs. sleeve lobectomy in patients younger and older than 70 years

Retrospective single institution analysis of all patients undergoing sleeve lobectomy or pneumonectomy between 2000 and 2005. Seventy-eight patients underwent pneumonectomy (65 patients <70 years, 13 patients >70 years) and 69 sleeve lobectomy (50 patients <70 years, 19 patients >70 years). Pre-existing co-morbidity, surgical indication and induction therapy was similarly distributed between treatment by age-groups. In patients <70 years, pneumonectomy and sleeve lobectomy resulted in a 30-day mortality of 3% vs. 0 and an overall complication rate of 26% vs. 44%, respectively. In patients >70 years, pneumonectomy and sleeve lobectomy resulted in a 30-day mortality of 15% vs. 0 and an overall complication rate of 23% vs. 32%. In both age groups, pneumonectomy was associated with more airway complications (NS) and a significantly higher postoperative loss of FEV(1) than sleeve lobectomy (P<0.0001, P<0.03). Age per se did not influence the loss of FEV(1) and DLCO for a given type of resection. Sleeve lobectomy may have a therapeutic advantage over pneumonectomy in the postoperative course of elderly patients.     

Tissue factor produced by the endocrine cells of the islets of Langerhans is associated with a negative outcome of clinical islet transplantation

There are strong indications that only a small fraction of grafts successfully engraft in clinical islet transplantation. One explanation may be the instant blood-mediated inflammatory reaction (IBMIR) elicited by tissue factor, which is produced by the endocrine cells. In the present study, we show that islets intended for islet transplantation produce tissue factor in both the transmembrane and the alternatively spliced form and that the membrane-bound form is released as microparticles often associated with both insulin and glucagon granules. A low-molecular mass factor VIIa (FVIIa) inhibitor that indirectly blocks both forms of tissue factor was shown in vitro to be a promising drug to eliminate the IBMIR. Thrombin-antithrombin complex (TAT) and FVIIa-antithrombin complex (FVIIa-AT) were measured in nine patients who together received 20 infusions of isolated human islets. Both the TAT and FVIIa-AT complexes increased rapidly within 15-60 min after infusion. When the initial TAT and FVIIa-AT levels were plotted against the increase in C-peptide concentration after 7 days, patients with an initially strong IBMIR showed no significant increase in insulin synthesis after 7 days. In conclusion, tissue factor present in both the islets and the culture medium and elicits IBMIR, which affects the function of the transplanted islets.     

Prevention of severe contractures might replace multilevel surgery in cerebral palsy: results of a population-based health care programme and new techniques to reduce spasticity

During the 1990s three new techniques to reduce spasticity and dystonia in children with cerebral palsy (CP) were introduced in southern Sweden: selective dorsal rhizotomy, continuous intrathecal baclofen infusion and botulinum toxin treatment. In 1994 a CP register and a health care programme, aimed to prevent hip dislocation and severe contractures, were initiated in the area. The total population of children with CP born 1990-1991, 1992-1993 and 1994-1995 was evaluated and compared at 8 years of age. In non-ambulant children the passive range of motion in hip, knee and ankle improved significantly from the first to the later age groups. Ambulant children had similar range of motion in the three age groups, with almost no severe contractures. The proportion of children treated with orthopaedic surgery for contracture or skeletal torsion deformity decreased from 40 to 15% (P = 0.0019). One-fifth of the children with spastic diplegia had been treated with selective dorsal rhizotomy. One-third of the children born 1994-1995 had been treated with botulinum toxin before 8 years of age. With early treatment of spasticity, early non-operative treatment of contracture and prevention of hip dislocation, the need for orthopaedic surgery for contracture or torsion deformity is reduced, and the need for multilevel procedures seems to be eliminated.     

Two corticosteroid-free regimens-tacrolimus monotherapy after basiliximab administration and tacrolimus/mycophenolate mofetil-in comparison with a standard triple regimen in renal transplantation: results of the Atlas study

BACKGROUND: The side effects associated with corticosteroids have led to efforts to minimize their use in renal transplant patients. In this study we compared two corticosteroid-free tacrolimus-based regimens with a standard triple therapy. METHODS: This was a 6-month, phase III, open-label, parallel-group, multicenter study. The total analysis set comprised 451 patients, randomized (1:1:1) to receive tacrolimus (Tac) monotherapy following basiliximab (Bas) administration (n=153), Tac/mycophenolate mofetil (MMF) (n=151), or, Tac/MMF/corticosteroids triple therapy as a control (n=147). RESULTS: The study was completed by 91.2% (triple therapy), 94.7% (Tac/MMF), and 82.4% (Bas/Tac) of patients. Patient baseline characteristics were similar in all groups. The incidences of biopsy-proven acute rejection were 8.2% (triple therapy), 30.5% (Tac/MMF), and 26.1% (Bas/Tac), p<0.001 (multiple test for comparison with triple therapy); Bas/Tac vs. Tac/MMF, p=ns. The incidences of corticosteroid-resistant acute rejection were 2.0%, 4.0%, and 5.2%, p=ns. Graft survival (95.9%, 96.7%, and 94.7%, p=ns) and patient survival (100%, 99.3%, and 99.3%, p=ns) were similar in all groups. Median serum creatinine at month 6 was 123.0 micromol/L (triple therapy), 134.7 micromol/L (Tac/MMF) and 135.8 micromol/L (Bas/Tac). The overall safety profiles were similar; differences (p<0.05) were reported for anaemia (24.5% vs. 12.6% vs. 14.5%), diarrhoea (12.9% vs. 17.9% vs. 5.9%), and leukopenia (7.5% vs. 18.5% vs. 5.9%) for the triple therapy, Tac/MMF, and Bas/Tac group, respectively. The incidences of new-onset diabetes mellitus were 4.6%, 7.1%, and 1.4%, respectively. CONCLUSION: Corticosteroid-free immunosuppression was feasible with the Bas/Tac and the Tac/MMF regimens. Both corticosteroid-free regimens were equally effective in preventing acute rejection, with the Bas/Tac therapy offering some safety benefits.     

Plasmin in Nephrotic Urine Activates the Epithelial Sodium Channel

Proteinuria and increased renal reabsorption of NaCl characterize the nephrotic syndrome. Here, we show that protein-rich urine from nephrotic rats and from patients with nephrotic syndrome activate the epithelial sodium channel (ENaC) in cultured M-1 mouse collecting duct cells and in Xenopus laevis oocytes heterologously expressing ENaC. The activation depended on urinary serine protease activity. We identified plasmin as a urinary serine protease by matrix-assisted laser desorption/ionization time of-flight mass spectrometry. Purified plasmin activated ENaC currents, and inhibitors of plasmin abolished urinary protease activity and the ability to activate ENaC. In nephrotic syndrome, tubular urokinase-type plasminogen activator likely converts filtered plasminogen to plasmin. Consistent with this, the combined application of urokinase-type plasminogen activator and plasminogen stimulated amiloride-sensitive transepithelial sodium transport in M-1 cells and increased amiloride-sensitive whole-cell currents in Xenopus laevis oocytes heterologously expressing ENaC. Activation of ENaC by plasmin involved cleavage and release of an inhibitory peptide from the ENaC γ subunit ectodomain. These data suggest that a defective glomerular filtration barrier allows passage of proteolytic enzymes that have the ability to activate ENaC.Nephrotic syndrome is characterized by proteinuria, sodium retention, and edema. Increased renal sodium reabsorption occurs in the cortical collecting duct (CCD),^1,2 where a rate-limiting step in transepithelial sodium transport is the epithelial sodium channel (ENaC), which is composed of the three homologous subunits: α, β, γ.³ENaC activity is regulated by hormones, such as aldosterone and vasopressin (AVP)^4,5; however, adrenalectomized rats and AVP-deficient Brattleboro rats are capable of developing nephrotic syndrome,^1,6 and nephrotic patients do not consistently display elevated levels of sodium-retaining hormones,^7,8 suggesting that renal sodium hyper-reabsorption is independent of systemic factors. Consistent with this, sodium retention is confined to the proteinuric kidney in the unilateral puromycin aminonucleoside (PAN) nephrotic model.^2,9,10There is evidence that proteases contribute to ENaC activation by cleaving the extracellular loops of the α- and γ-subunits.^11–13 Proteolytic activation of ENaC by extracellular proteases critically involves the cleavage of the γ subunit,^14–16 which probably leads to the release of a 43-residue inhibitory peptide from the ectodomain.¹⁷ Both cleaved and noncleaved channels are present in the plasma membrane,^18,19 allowing proteases such as channel activating protease 1 (CAP1/prostasin),²⁰ trypsin,²⁰ chymotrypsin,²¹ and neutrophil elastase²² to activate noncleaved channels from the extracellular side.^23,24 We hypothesized that the defective glomerular filtration barrier in nephrotic syndrome allows the filtration of ENaC-activating proteins into the tubular fluid, leading to stimulation of ENaC. The hypothesis was tested in the PAN nephrotic model in rats and with urine from patients with nephrotic syndrome.     

Serum osteoprotegerin and its relationship with bone mineral density and markers of bone turnover

Introduction: The purpose of this study was to compare age-related differences in osteoprotegerin (OPG) in relationship with BMD and the serum bone markers osteocalcin (OC), collagen crosslinks (CTX), and tartrate-resistant acid phosphatase 5b (TRACP-5b). Methods: Data were derived from a cross-sectional study on bone health in a random sample of community-dwelling adults aged 30 to 85 years in the Reykjavik area in Iceland. All subjects had whole body, hip, and lumbar spine BMD measured (by DXA), gave blood samples, and answered a thorough questionnaire on medications and medical history. We assessed relationships using the Spearman correlation coefficient, partial correlation, and multivariable linear regression. Men and women were analyzed separately. Results: Of 2,310 subjects invited over 2 years, 1,630 participated. After excluding individuals with diseases and medications affecting bone metabolism, 517 women (age 56.1 ± 16.9 years) and 491 men (age 58.7 ± 14.9 years) remained for analysis. OPG increased steadily with age in both genders without a gender difference. In women, BMD at all sites declined steadily after age 50. In men, BMD remained relatively stable until age 70, after which it declined significantly. After controlling for age, BMI, and other confounding variables, OPG showed only a borderline positive relationship with whole body BMD in men (P=0.10), but the relationship was nonsignificant in women. In multivariable models, OPG was inversely related to TRACP-5b (P=0.002) and positively with OC (P=0.007), the OC/TRACP-5b (P=0.001) and OC/CTX (P=0.02) ratios in women. Among men, multivariable models showed a positive association between OPG and OC (P=0.05) and OC/TRACP-5b (P<0.009). Conclusions: We conclude that serum OPG levels are associated with a profile of bone turnover markers favoring bone formation, suggesting that OPG may be protective against age-related bone loss. Longitudinal studies are needed to address that issue.