Refractory Ascites After Liver Transplantation: An Analysis of 1058 Liver Transplant Patients at a Single Center

A retrospective study of 1058 liver transplant recipients was performed to determine: (i) the incidence, etiology, timing, clinical features and treatment of refractory ascites (RA), (ii) risk factors for RA development, (iii) predictors of RA disappearance, (iv) predictors of survival following RA and (v) the impact of RA on patient survival. Sixty-two patients (5.9%) developed RA and its disappearance occurred in 27/62 cases. Patients having hepatitis C virus (HCV) had a significantly higher hazard rate of developing RA (p < 0.00001). No other baseline characteristic was associated with RA. Cox stepwise regression analysis of the hazard rate of RA disappearance found two significant factors: HCV recurrence as the reason for developing RA implied a poorer outcome (p = 0.006), whereas an unknown reason implied a favorable outcome (p = 0.02). In addition, survival following RA was significantly poorer among patients having bacterial peritonitis or HCV recurrence. Finally, the mortality rate was significantly (nearly 8.6 times) higher in patients following RA development while it was ongoing (p < 0.00001); however, if the RA disappeared, then the additional risk of death also disappeared. This study illustrates the importance of developing an optimal treatment strategy to (i) effectively treat RA if it develops and (ii) prevent hepatitis C recurrence.     

Assessment of neutrophil leukocyte secretory response to fMLP in whole blood in vitro.

A simple, precise method has been developed for assessing neutrophil secretory responses (release of vitamin B12 binding protein from specific granules) to challenge of aliquots of whole blood with the bacterial chemotactic peptide N-formylmethionyl-leucyl-phenylalanine (fMLP). Dose-response studies performed on blood from normal healthy volunteers showed higher maximal secretory responses in males than females (33.3 +/- SEM 2.2 vs. 27.4 +/- 2.5, P less than .005) a left shift in dose-response curves after feeding compared to fasting (P less than .005), spontaneous up-regulation of responses in blood incubated at 37 degrees C for 1 h, and marked upregulation in response to preincubation with endotoxin. This whole blood challenge method may be used to study neutrophil responses in groups of individuals or patients without the confounding effects of changes in cell responses resulting from cell isolation procedures. The method may also be used as a bioassay for neutrophil-activating factors.     

Renal transplantation from elderly living donors

A worldwide shortage of cadaveric donors has led to the increased utilization of elderly living donors, with controversial results. In an attempt to assess the effect of donor age on graft survival and subsequent renal function, we analyzed our clinical results in 276 consecutive recipients of living related renal transplants spanning both the cyclosporine and the azathioprine eras, of whom a total of 44 recipients received kidneys from donors over 55 years old. All recipients were otherwise similar in age, race, haplotype mismatch, number of retransplants, and number of pretransplant transfusions, apart from an increased number of diabetics among the CsA-treated recipients of elderly kidneys (38% vs. 14%). The cumulative patient and graft survival rates at 1 and 5 years were independent of donor age whether CsA or AZA was utilized. Nor was the incidence of rejection or infection significantly different in the older donor group when compared with the younger cohort. Short-term and intermediate-term renal function, as assessed by serum creatinine, was however poorer but stable in the older donor group when compared with the younger one. The mean serum creatinine levels at 1 year in the CsA- and AZA-treated recipients of kidneys from older donors were 2.4 and 2.0 mg/dl, respectively, compared with 1.6 and 1.4 mg/dl, respectively, when the donor age was less than 55 years (P less than 0.001). Since renal function at the end of the first posttransplant year is considered a determinant of long-term graft survival, this is a cause for concern, but in view of the universal shortage of organs and the negligible morbidity to donors, renal transplantation from elderly living donors remains an acceptable practice.     

The 1989 report of the North American Pediatric Renal Transplant Cooperative Study

This report of the North American Pediatric Transplant Cooperative Study summarizes data contributed by 57 participating centers on 754 children with 761 transplants from 1 January 1989 to 16 February 1989. Data collection was initiated in October 1987 and follow-up of all patients is ongoing. Transplant frequency increased with age; 24% of the patients were less than 5 years, with 7% being under 2 years. Common frequent diagnoses were: aplastic/dysplastic kidneys (18%), obstructive uropathy (16%), and focal segmental glomerulosclerosis (12%). Preemptive transplant, i.e., transplantation without prior maintenance dialysis, was performed in 21% of the patients. Dialytic modalities pretransplant were peritoneal dialysis in 42% and hemodialysis in 25%. Bilateral nephrectomy was reported in 29%. Live-donor sources accounted for 42% of the transplants. Among cadaveric donors, 41% of the donors were under 11 years old. During the first post-transplant month, maintenance therapy was used similarly for live-donor and cadaver source transplants, with prednisone, cyclosporine, and azathioprine used in 93%, 83%, and 81%, respectively. Triple therapy with prednisone, cyclosporine, and azathioprine was used in 78%, 75%, and 75% of functioning cadaver source transplants at 6 months, 12 months, and 18 months as opposed to 60%, 63%, and 54% for live-donor procedures, with single-drug therapy being uncommon. Rehospitalization during months 1–5 occurred in 62% of the patients, with treatment of rejection and infection being the main causes. Additionally, 9% were hospitalized for hypertension. During months 6–12 and 12–17, 30% and 28% of the patients with functioning grafts were rehospitalized. Times to first rejection differed significantly for cadaver and live-donor transplants. The median time to the first rejection was 36 days for cadaver transplants and 156 days for live-donor transplants. Overall, 57% of treated rejections were completely reversible although the complete reversal rate decreased to 37% for four or more rejections. One hundred and fifty-two graft failures had occurred at the time of writing, with a 1-year graft survival estimate of 0.88 for live-donor and 0.71 for cadaver source transplants. In addition to donor source, recipient age is a significant prognostic factor for graft survival. Among cadaver donors, decreasing donor age is associated with a decreasing probability of graft survival. Thirty-five deaths have occurred; 16 attributed to infection and 19 to other causes. The current 1-year survival estimate is 0.94. There have been 9 malignancies.A list of all participating centers and the names of the investigators is printed on pages 552–553     

Discovery of potent and selective inhibitors of procollagen C-proteinase for the treatment of fibrotic disorders

Introduction   Fibrosis is a component of many tissue pathologies leading to loss of normal tissue function, primarily due to excessive collagen deposition. Collagen is deposited following cleavage of the C- and N- terminal peptides from the pro-collagen molecule. The cleavage of the globular C-peptide by PCP reduces solubility of the fibrillar collagen molecule, resulting in deposition of insoluble collagen. Increased insoluble collagen deposition is a feature of all organ fibroses, with inhibition of this process, a key potential anti-fibrotic mechanism. The aim of this work was to discover potent and selective PCP inhibitors as experimental, topically applied, anti-fibrotic drugs for clinical evaluation.
Materials and methods   PCP was cloned from human osteosarcoma cells and enzymatic activity demonstrated using a PCP-specific peptide cleavage assay. Activities were confirmed by measuring cleavage of [³H]C-peptide from type-I pro-collagen. A cell-based fibroplasias model was employed to demonstrate compound efficacy using collagen deposition, liberated C-peptide and histological endpoints. The activities of PCP inhibitors in fibroblast and epithelial in vitro cell proliferation and migration assays, and selectivity vs. a panel of MMPs were also determined.
Discussion   In summary, we have identified and characterized potent and selective inhibitors of PCP for progression to clinical studies for investigation as a treatment paradigm for fibrotic disease.  

  Results     

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