Acute graft pyelonephritis and long-term kidney allograft outcome

BACKGROUND: Long-term graft function is the result of multiple parameters, including both immune and non-immune components, which have a beneficial or detrimental potential. Among these, despite its frequency and theoretical interest (expression of "danger signals" in the graft itself), the effects of acute graft pyelonephritis (AGPN) on immediate and long-term outcome have not been studied in a large series. This article reviews a cohort of 1387 consecutive primary renal transplant recipients. METHODS: The objective of the study was to define the risk factor for AGPN, the risk profile for recurrence, and the impact of AGPN on long-term graft survival. According to a higher risk for AGPN in females during their follow-up, statistical analyses (Cox model, and multiple regression analysis) were performed by recipient sex strata. RESULTS: Multivariate analysis showed that CMV infection was the only risk factor for AGPN occurrence. AGPN occurred in 13% of the graft recipients during their follow-up. Taken as a whole, AGPN was not associated with a significantly poor long-term outcome. However, when assessed in more detail, the outcome of this population was found to be more complex and to depend on several factors. Early AGPN (during the first 3 months) was significantly detrimental for graft outcome, independently of acute rejection episodes. Moreover, E. coli involvement in a first episode was linked to an increased AGPN recurrence. CONCLUSION: This analysis did not support the concept that with current immunosuppression, strong "danger signals" such as those derived from bacteria within an allograft, are instrumental in initiating acute or chronic rejection.     

Clinical validation of the new ELSA-CA 125 II assay: Report of a european multicentre evaluation

The ELSA-CA 125 II is a second-generation radioimmunoassay for the quantification of CA 125 in serum. In a multicentre study involving 49 follow-ups of patients with ovarian cancers, and 880 other patients, 2.8% of healthy persons, 25% of 149 patients with benign gynaecological diseases and 39% of 82 patients with benign non-gynaecological diseases had CA 125 levels above 35 U/ml. Using the 35 U/ml cut-off, sensitivities among epithelial ovarian cancers were found to be 85% in serous tumors, 41% in mucinous tumors and 83% in other types. During follow-up of patients with serous ovarian cancers, we observed an equivalent behaviour of both assays—first- and second-generation—with the clinical evolution. We also compared results obtained with other assays commercially available; these were significantly different when a polyclonal antibody was used in the sandwich assay. © 1995 Wiley- Liss, Inc.     

Prevention of lupus diseases in MRL/1, NZBxNZW, and BXSB mice treated with a cyclophosphazene derived drug

A polyclonal activation of lymphocytes (PA) has been suggested to play a pathogenic role in autoimmune and immune complex diseases, particularly in mouse lupus. "DIAM 4," a cyclophosphazene derived drug, selected on the basis of its ability to modulate a PA has been used to treat female MRL/1, female NZBxNZW, and male BXSB mice. In these three strains of mice, the treatment was found to induce an inhibition of the PA, to prevent the increase of anti-DNA antibody levels and the simultaneous decrease of C3 levels, to prevent the appearance of proteinuria, the deposition of immune complexes in glomeruli, and the development of kidney lesions. Moreover in MRL/1 mice, lymphoproliferation was prevented. These results suggest that drugs able to modulate a PA might be efficient in the treatment of mouse lupus nephritis. Such a principle of immunomodulation might open the way to new possibilities of treatment of lupus and other immune complex diseases.     

t( 12;21): A new recurrent translocation in acute lymphoblastic leukemia

A t(12;21)(p11 -p12;q22) was detected by chromosome painting in three patients with acute lymphoblastic leukemia (ALL) among eight ALL cases with 12p- abnormalities. The three leukemias had similar immunophenotypes (DR+, CD10 +, CD19 + ). Fluorescence in situ hybridization (FISH) experiments using YAC clones from 21q21-q22 were performed to better localize the breakpoint on chromosome 21. This breakpoint was localized to 21q22.2 in one patient. Although only one case of ALL with t( 12;21) has been reported previously, the present results suggest that t( 12;21) is a recurrent translocation in ALL. Genes Chrom Cancer 9:186-191 (1994). © 1994 Wiley-Liss, Inc.     

Expression of complement alternative pathway proteins by endothelial cells. Differential regulation by interleukin 1 and glucocorticoids

We have studied the secretion of proteins of the alternative pathway of complement C3, factor B and factor H by human umbilical vein endothelial cells (HUVEC). Results showed that factor H and factor B are quantitatively secreted in abundance whereas C3 could only be detected when the cells are maintained in culture during long periods of time. Interferon-γ stimulated factor H, factor B and, to a lesser extent, C3 secretions. Interleukin (IL) 1 had a differential effect on spontaneous C3, factor B and factor H secretions. In the presence of IL 1, there was a significant secretion of C3 occurring within a short period of culture. IL 1 also stimulated factor B secretion. There was a synergistic stimulating effect between IL 1 and interferon-γ to bring C3 and factor B productions by HUVEC to very high levels. In contrast, factor H secretion was consistently inhibited by IL 1. Local increase in C3 and factor B secretions by endothelial cells in the presence of IL 1 may have important implications in the inflammatory reaction. In striking contrast, the glucocorticoid dexamethasone (DXM) had modulatory effects which are consistent with its anti-inflammatory properties. DXM, at therapeutic concentrations, decreased C3 and factor B secretions and increased factor H secretion. Local modulation of complement protein secretion by DXM appears to be a new mechanism by which this glucocorticoid may control inflammation.     

Induction of similar features of apoptosis in human and bovine vascular endothelial cells treated by 7-ketocholesterol

Cholesterol oxides have numerous cytotoxic effects and those oxidized in the C7 position have been shown to induce apoptosis in bovine aortic endothelial cells (BAEC). The aim of the present study was to determine whether apoptosis also occurs in human vascular endothelial cells (HUVEC) treated with 7-ketocholesterol. To this end, cultured BAEC and HUVEC were incubated for 48 h with 7-ketocholesterol (concentration range 5–80 μg/ml) and the characteristics of cell death were assessed by various methods: counting of adherent and non-adherent cells; analysis of DNA fragmentation pattern; and morphological study by light, fluorescence, and electron microscopy. The 7-ketocholesterol treatment was accompanied by a decrease in the number of adherent cells and an increase in the number of non-adherent cells. Apoptotic cells, recognized by fragmented and/or condensed nuclei after staining with Hoechst 33342 or Giemsa, were mainly detected among non-adherent cells, and agarose gel electrophoresis revealed a typical internucleosomal DNA fragmentation among 7-ketocholesterol-treated cells. The DNA fragmentation was no longer detected when HUVEC and BAEC were simultaneously incubated with 0·5 mmol/l zinc chloride, which is known to inhibit Ca²⁺/Mg²⁺-dependent endonucleases. Finally, the ultrastructural abnormalities observed by electron microscopy in both 7-ketocholesterol-treated HUVEC and BAEC were remarkably similar and were mainly characterized by condensed chromatin, altered mitochondria, disturbed organization of the cytoskeleton, and vacuoles containing myelin figures and/or cell debris; apoptotic bodies were also frequently detected. It is concluded that 7-ketocholesterol constitutes a potent inducer of apoptosis in endothelial vascular cells of both bovine and human origin, suggesting that cholesterol oxides may be involved in the early steps of the atherosclerotic process in humans. © 1997 John Wiley & Sons, Ltd.     

FISH analysis of translocations involving the short arm of chromosome 9 in lymphoid malignancies

Deletion of the short arm of chromosome 9 (9p), resulting in the loss of the p16^INK4a/MTS1 gene, now called CDKN2, has been found to occur frequently in acute lymphoblastic leukemia, even in the absence of a microscopically visible deletion. In this study, we have used YAC probes encompassing the CDKN2 locus to analyze by fluorescence in situ hybridization patients with leukemia and lymphoma and translocations involving 9p in order to establish the CDKN2 status in relation to the karyotype. We found that, in leukemic cells exhibiting loss of heterozygosity at the CDKN2 locus, the deleted allele was from the cytogenetically normal chromosome 9, whereas the other allele was located on a rearranged chromosome. This finding suggests that CDKN2 gene loss is nonrandomly associated with 9p translocation in lymphoid proliferations. Genes Chromosom. Cancer 19:273–277, 1997. © 1997 Wiley-Liss, Inc.     

Clinical update: Spironolactone and altizide as monotherapy in systemic hypertension

A large-scale, open, nonrandomized, multicenter, 90-day study of the safety and efficacy of a thiaride diuretic and aldosterone antagonist combination (Aldactazine^®, 25 mg spironolactone and 15 mg altizide, 1/day) as monotherapy was performed in 946 patients with mild to moderate hypertension (diastolic blood pressure [BP] between 90 and 120 mm Hg). Adverse effects were assessed, and body weight, heart rate, serum potassium, creatinine and uric acid measurements were monitored. On day 45 of the study, BP was normalized (diastolic BP ≤90 mm Hg) in 72% of the patients. The dose was increased to 2 tablets per day in the patients whose BP did not reach normal levels. By the end of the study, BP was controlled in 83% of the patients. No significant changes were noted in body weight, heart rate or laboratory values; however, treatment had to be discontinued in 6 patients because of hypokalemia (n = 4) or elevated serum creatinine levels (n = 2). Serum uric acid levels were increased in 5.5% of patients. The rate of adverse effects, as reported by the patients, was low (5%). Thus, this study demonstrates that diuretics, especially the combination of a thiazide diuretic and aldosterone antagonist, remain a safe, effective and economical therapy for patients with mild to moderate hypertension.     

Cadaveric renal transplantation after 60 years of age

We report the outcome of 121 cadaveric renal transplants performed in our institution between September 1985 and April 1992 in 117 patients, aged 60–71 years (mean 63 years) at the time of transplantation. Compared to 640 patients 20–59 years of age transplanted during the same study period, a nonstatistically significant difference was observed in the 5-year actuarial patient (80% and 90%, respectively, in recipients over and under 60 years of age) and transplant (80% and 72%, respectively, in recipients over and under 60 years oaf age) survival rates. However, elderly patients had significantly lower survival than recipients 20–29 years of age (P<0.009). Fourteen patients died (all but one with a functioning graft) due to cardiovascular diseases (5%; 42.8% of total deaths), infections (3%; 28.6% of total deaths), and gastrointestinal complications (3%; 28.6% of total deaths). Younger patients showed a similar and nonsignificantly different incidence of cardiovascular- (35%) and infectious- (30%) related deaths. The incidence of acute rejection episodes and cytomegalovirus (CMV) infectious episodes was 27% and 24%, respectively, during the 1st post-transplant year. Ongoing acute rejection and CMV infectious episodes were significantly higher in patients who died than in those still alive (P<0.002 and P<0.02, respectively). Cyclosporin maintenance therapy was well tolerated in all patients but one, and 64% of the patients could be maintained without steroids. These data indicate that cadaveric renal transplantation is a safe and effective procedure in the management of chronic renal failure of selected patients 60 years of age or older.     

Modulation of polyclonal activation of lymphocytes by cyclophosphazenic compounds bearing ethylene-imino groups and vectorized by polyamines

Cyclophosphazenic compounds bearing ethylene-imino groups are cytocydal chemicals which can modulate polyclonal activation of lymphocytes (PAL) and prevent the development of murine lupus. The effects on PAL of the different parts of these chemicals and of vectorization by polyamines have been investigated by treating lipopolysaccharide injected C57Bl/6 mice with various cyclophosphazenic compounds and thiotepa. The immune effects of the cyclophosphazenic substances have been found to be mediated by ethylene-imino groups and to be modulated by polyamine vectorization. These compounds might represent a new class of drugs for treatment of immune mediated diseases of the lupus type.