Current thinking on chronic renal allograft rejection: issues, concerns, and recommendations from a 1997 roundtable discussion

Chronic rejection accounts for most renal allograft losses after the first year posttransplantation. On March 24 and 25, 1997, a roundtable of five transplant surgeons, two nephrologists, and one pathologist assembled in Dallas, Texas, to review critical issues surrounding chronic renal allograft rejection. This article summarizes the presentations and relevant discussions of this meeting regarding the cause of chronic rejection, clinical diagnoses, risk factors, future prospects for intervention strategies, and general recommendations for the transplant community. Growing evidence indicates that chronic rejection is the aggregate sum of irreversible immunologic and nonimmunologic injuries to the renal graft over time. A history of acute rejection episodes and inadequate immunosuppression, likely attributable to inconsistent cyclosporine exposure or poor patient compliance, are among the most recognizable immunologic risk factors for chronic rejection. Donor organ quality, delayed graft function, and other donor and recipient variables leading to reduced nephron mass are nonimmunologic factors that contribute to the progressive deterioration of renal graft function. Clinical management of renal transplant recipients should incorporate both immunologic- and nonimmunologic-based intervention strategies aimed at minimizing risk factors to thwart the progression of chronic rejection and improve long-term allograft and patient survival.     

Anabolic and catabolic mRNA levels of the intervertebral disc vary with the magnitude and frequency of in vivo dynamic compression.

The goal of this study was to characterize the anabolic and catabolic mRNA response of the disc to dynamic loading to determine if variations in the magnitude and/or frequency of loading could elicit different cellular responses. Sixty-eight Wistar rats were instrumented with an Ilizarov-type device spanning caudal disc 8-9. Seventy-two hours after surgery, animals were anesthetized and loaded at either 1 or 0.2 MPa at a frequency of 1, 0.2 or 0.01 Hz for 2 h (6 groups). The surgical control (Sham) animals underwent anesthesia with no loading. Loaded (c8-9) and internal-control discs (c6-7 and c10-11) were dissected and annulus and nucleus tissue were separately analyzed by real-time RT-PCR for levels of anabolic (collagen-1A1, collagen-2A1, aggrecan) and catabolic (MMP-3, MMP-13, ADAMTs-4) mRNA. In the nucleus, a frequency-dependent response was seen at 1 MPa with anabolic genes stimulated at 0.01 Hz and catabolic genes at 1 Hz. In the annulus all frequencies resulted in significant up-regulation of catabolic mRNA at 1 MPa loading. In general loading at 0.2 MPa or 0.2 Hz had little effect on gene expression. The results suggest that gene expression of the annulus appears to be more dependent on the magnitude of applied stress, while the nucleus is both magnitude- and frequency-dependent.     

Interleukin-6 predicts hypoalbuminemia, hypocholesterolemia, and mortality in hemodialysis patients

Low serum albumin and low serum cholesterol levels are among the most consistent predictors of mortality in patients with end-stage renal disease (ESRD) undergoing hemodialysis. Hypoalbuminemia is often interpreted as a marker of poor nutrition, but serum albumin and cholesterol levels can also be low as part of a cytokine-mediated acute-phase reaction to acute or chronic inflammation. Here we report the results from a 900-day prospective study designed to determine whether tumor necrosis factor-alfa (TNF-alpha) and interleukin-6 (IL-6) predict serum albumin and cholesterol levels and mortality in a group of 90 ambulatory, adult hemodialysis patients with no acute infection, hospitalization or surgery, and no known acquired immunodeficiency syndrome (AIDS), malignancy, or liver disease. Measurable levels of TNF-alpha and/or IL-6 were found in 89 of 90 patients. Significant relationships were found between TNF-alpha and IL-6 and the degree of hypoalbuminemia and dyslipoproteinemia. IL-6 was the strongest predictor of mortality in univariate and multivariate analysis, followed by age, albumin level, and body mass index (BMI). Although the cause of hypercytokinemia was not addressed in this study, the data support the view that hypoalbuminemia and hypocholesterolemia are negative acute-phase responses to inflammatory stimuli. These results suggest that efforts to identify the nature of the stimuli for cytokine production and to lower cytokine levels in hemodialysis patients might be effective in improving the survival of patients undergoing hemodialysis.     

Prognosis of patients with acute renal failure requiring dialysis: results of a multicenter study

Despite several decades of clinical experience, the mortality rate for patients with acute renal failure (ARF) requiring dialysis remains high, and the evaluation of the patients prognosis has been difficult. To date, the Acute Physiology and Chronic Health Evaluation II (APACHE II) scoring system has been used more frequently for prediction in studies of ARF than any other scoring system, but has not been prospectively validated in controlled multicenter studies of this entity. In a multicenter, prospective, controlled trial evaluating the use of biocompatible hemodialysis membranes (BCMs) in patients with ARF, we evaluated the extent to which the APACHE II scoring system, based on the physiological variables in the 24 hours before the onset of dialysis and the presence or absence of oliguria, is predictive of outcome. Analysis of survival and recovery of renal function for the 153 patients treated in this study show that APACHE II scores are predictive both of survival and recovery of renal function, whether analyzed separately by type of dialysis membrane used (BCM or bioincompatible [BICM]) or for both groups combined (all P < 0.01). There was no evidence of a significant center effect or interaction of APACHE II score with dialysis membrane in our study. After adjusting for the APACHE II score, there was a positive effect of the BCM on both probability of survival (P < 0.05) and recovery of renal function (P < 0.01). In patients dialyzed with BCMs, oliguria at onset of dialysis had an adverse effect on both survival and recovery of renal function (both P < 0.01). Receiver operator curves (ROCs) using APACHE II score and the use of BCMs in nonoliguric patients yielded a statistically significant improvement versus the use of APACHE II score alone in the area under the curve (AUC) for survival (0.747 to 0.801; P < 0.05) and recovery of renal function (0.712 to 0.775; P < 0.05). We conclude that the use of the APACHE II score determined at the time of initiation of dialysis for patients with ARF is a statistically significant predictor of patient survival and recovery of renal function. The use of the APACHE II score measured at the time of dialysis initiation, especially when modified by the presence or absence of oliguria, should help in predicting outcome when evaluating interventions for patients with ARF.     

Tube pedicle flap in the management of a Grade III C lower limb injury.

Salvage of a Grade III C lower limb injury is a challenging problem. Apart from microsurgical revascularisation, they frequently need soft tissue coverage procedures. Due to the magnitude of the injury, local flaps from adjacent tissues may not be available and microsurgical free flaps are the flaps of choice. We present an instance where the defect in the middle third of a revascularised leg was covered by a tube pedicle flap raised from the groin and transferred, with the wrist as the carrier. This was chosen because of the below knee amputation on the opposite side combined with long segment circumferential loss of skin in the affected extremity and paucity of vein graft sources. Thus the reconstruction of a limb which was saved by microsurgery was completed by tube pedicle flap. In exceptional circumstances 'old' techniques are still useful.     

Effects of a new cardiomyoplasty technique on cardiac function

OBJECTIVE: The current cardiomyoplasty technique was modified to maintain the resting tension of the latissimus dorsi muscle and to prevent lateral movement of the heart during muscle stimulation. The aim of this study is to compare the short term hemodynamic effects of the new cardiomyoplasty wrap (W1) with those of the clinically applied cardiomyoplasty wrap (W2). Preliminary indications of the long-term hemodynamic effects of W1 are presented. METHODS: In three acute experiments in sheep mean central venous pressure (MCVP), mean arterial pressure (MAP), mean cardiac output (MCOP), mean left ventricular systolic pressure (MLVSP), and mean left ventricular diastolic pressure (MLVDP) were measured for 30s before and five minutes after applying each procedure with and without stimulation of the muscle graft. The same parameters were also recorded 5min after removing each muscle wrap. Hemodynamic changes associated with unstimulated muscle wraps were compared to the baseline data. Hemodynamic effects of muscle stimulation were determined by comparing the assisted to the preceding unassisted cardiac cycle. The long-term effects of W1 on the hemodynamics of another three sheep were studied at 6-12months after the operation. The viability of the muscles used in the chronic experiments were evaluated by morphometric analysis. RESULTS: Unstimulated W2 significantly increased mean central venous pressure and reduced mean cardiac output. It also increased mean left ventricular diastolic pressure and reduced peak negative dP/dt. Unstimulated W1 had no deleterious effect on mean central venous pressure, mean left ventricular diastolic pressure or peak -dP/dt, but it also reduced mean cardiac output and increased mean left atrial pressure (MLAP). Synchronised muscle stimulation, in both techniques, augmented the mean arterial pressure, mean cardiac output and mean left ventricular systolic pressure. In W2, however, myostimulation was also associated with a significant increase of the mean left ventricular diastolic pressure. In two long-term experiments significant hemodynamic assistance was observed at 6months and at 1yr after W1. In those sheep 68% of the cross-sectional area of the muscle was well preserved. CONCLUSIONS: Unstimulated cardiomyoplasty wraps acutely impair left ventricular function in sheep. The new technique, however, may offer significant long-term hemodynamic assistance and adequate preservation of the structural and functional integrity of the muscle flap for up to 1yr.     

A model for estimating the potential costs and savings of osteoporosis prevention strategies

A model was developed which estimates the costs of osteoporosis risk evaluation and treatment, and the resulting savings in terms of reduced fracture frequency, for the adult female population of the United States. In the absence of treatment, the model predicts 1.44 million fractures will occur annually from non-violent causes. Treatment of all women beginning at age 50 with an agent that slows bone loss by 50% would reduce the number of these fractures by 0.59 million. Selective treatment of the 47% of women at the greatest fracture risk would reduce the number of fractures by 0.45 million, but would only cost 47% as much as treating all women. Additional data are required before the model can be used to evaluate specific treatment regimens. However, it appears that selective treatment of those at highest risk would yield the greatest benefit to cost ratio, if only benefits related to reduced fracture frequency are considered.     

Annexin V for flow cytometric detection of phosphatidylserine expression on B cells undergoing apoptosis

Apoptosis, or programmed cell death, is a general mechanism for removal of unwanted cells from the immune system. It is characterized by chromatin condensation, a reduction in cell volume, and endonuclease cleavage of DNA into oligonucleosomal length fragments. Apoptosis is also accompanied by a loss of membrane phospholipid asymmetry, resulting in the exposure of phosphatidylserine at the surface of the cell. Expression of phosphatidylserine at the cell surface plays an important role in the recognition and removal of apoptotic cells by macrophages. Here we describe a new method for the detection of apoptotic cells by flow cytometry, using the binding of fluorescein isothiocyanate-labeled annexin V to phosphatidylserine. When Burkitt lymphoma cell lines and freshly isolated germinal center B cells are cultured under apoptosis inducing conditions, all cells showing chromatin condensation strongly stain with annexin V, whereas normal cells are annexin V negative. Moreover, DNA fragmentation is only found in the annexin V-positive cells. The nonvital dye ethidium bromide was found to stain a subpopulation of the annexin V-positive apoptotic cells, increasing with time. Our results indicate that the phase in apoptosis that is characterized by chromatin condensation coincides with phosphatidylserine exposure. Importantly, it precedes membrane damage that might lead to release from the cells of enzymes that are harmful to the surrounding tissues. Annexin V may prove important in further unravelling the regulation of apoptosis.