Serum trough levels in the early post-renal transplant course were set at 175 to 200 ng/mL in spite of a standard drug administration regimen by selecting once- v twice-daily dosing intervals, in order to attempt to compensate for differences in drug clearance rates, which might determine trough values. When pretransplant pharmacokinetic parameters were correlated with posttransplant events, patients dosed twice daily were at greater risk of rejection if they displayed a low AUC IV, a rapid CL, or a large Vd. On the other hand, once-daily-treated patients experienced infections if the AUC PO or Cmax was large or drug clearance was low. Patients treated twice daily displayed hepatotoxicity if their AUC IV was high and their Vd and CL low. Nephrotoxicity was seen in patients of both groups with high AUC IV and low CL. Comparison of pre- v posttransplant pharmacokinetic profiles correlated with rejection if the postoperative study showed a reduced Cmax and with hepatotoxicity if the AUC PO and F values were higher than preoperatively. The overall results suggested (although cadaver transplant outcome did not confirm) a lower incidence of rejection on the twice-daily compared with the once-daily regimen. There was no significant difference in the incidence of toxic complications between the groups. However, all of the patients who experienced nephrotoxicity during twice-daily therapy improved when converted to once-daily treatment. The present study suggests that specific values can be established for pharmacokinetic parameters, which would permit clinicians to individually tailor posttransplant immunosuppression to optimize the therapeutic effects of CsA.

Adolescent↗

PubMed1985

Herpes virus infection prevalence in regular haemodialysis patients--a comparative evaluation of complement fixation, indirect immunofluorescence and Elisa tests.

The presence and titres of specific serum IgG and IgM antibodies to cytomegalovirus, herpes simplex virus and varicella-zoster virus were evaluated in 50 haemodialysis patients by complement fixation, immunofluorescence and Elisa tests. A second serum sample was tested in 24 patients after four weeks. Specific serum IgG antibodies to Epstein-Barr virus were also measured by immunofluorescence in 26 patients. By immunofluorescence and Elisa tests, the prevalence of cytomegalovirus, herpes simplex virus and Epstein-Barr virus infection is approximately 100 per cent, and varicella-zoster virus 60 per cent. High titres of IgG specific antibodies found by Elisa tests, detection of IgM antibodies in 16-18 per cent of patients and sero-conversion in 25 per cent of patients, suggests continuous antigenic stimulation.

Adult↗

PubMedDate not supplied

Low intrapatient variability of blood cyclosporine levels is correlated with excellent graft survival.

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Adult↗

PubMedDate not supplied

Molecular analysis of uromodulin and SAH genes, positional candidates for autosomal dominant medullary cystic kidney disease linked to 16p12.

BACKGROUND: The location of a second genetic locus for autosomal dominant medullary cystic kidney disease (ADMCKD) at chromosome 16p12 led us to further investigate the molecular analysis of the critical region where two genes coding for uromodulin and SA proteins with renal specific functions, UMOD and SAH, are localized. METHODS: We characterized the intron-exon boundary sequences by screening phage and BAC DNA genomic clones for the development of new molecular tools functional to the mutation analysis of UMOD and SAH genes. RESULTS: No consistent mutations for ADMCKD2 were found in the UMOD and SAH genes. We identified a silent polymorphism in the UMOD gene at codon C174 which co-segregates with the disease in the ADMCKD2 family. CONCLUSIONS: This study excludes the involvement of uromodulin and SAH genes in ADMCKD2, and provides new tools for their molecular analysis in other diseases.

Chromosome Mapping↗

PubMedDate not supplied

[Thermal energy balance during hemodialysis: the role of the filter membrane].

BACKGROUND: Body temperature tends to increase during conventional haemodialysis; this might interfere with normal cardiovascular response to dialytic ultrafiltration, thus facilitating the occurrence of symptomatic hypotension. Putative factors responsible for changes in thermal balance during haemodialysis include heat load from the dialysis bath, reduction in convective heat loss secondary to skin vessel vasoconstriction, heat overproduction due to central stimulation by bioincompatibility reactions to the filter membranes. The aim of the present study was twofold: to define thermal energy balance (ET) during dialysis and to investigate the effect of membrane bioincompatibility on energy balance METHODS: We measured ET in 12 patients (9M, 3F) during two identical dialysis sessions, differing only in the membrane composition of the filters used: cuprophane 1.3- 1.6 mq and LF polysulphone 1.3- 1.6 mq. Thermal energy balance studies were performed by the Blood Temperature Monitor (Fresenius Medical Care) under conditions in which the core temperature of the patients was maintained unchanged from the start to the end of the dialysis procedure. RESULTS: Arterial blood temperatures were constant, while dialysate and venous blood temperatures progressively decreased (from 36.9 to 35.4 C and from 36.5 to 35.1 C for cuprophane; from 36.9 to 35.2 and from 36.9 to 35.1 for polysulphone membrane). Mean thermal energy transfer was negative (removal of energy from the patients to the extracorporeal circuit) with both filters, equal to 146 KJ with cuprophane and to 163 KJ with polysulphone. When a stepwise multiregression analysis was applied, hourly energy transfer (ET) was significantly and independently correlated with both ultrafiltration rate (UF=% b.w.) and heart rate changes (HR) according to the equation: ET= -92.03+41.29 UF+1.04 HR (p<0.0003). Conclusions. In this study we present experimental evidence that increased body temperature during dialysis is not caused by heat load from the dialysis bath, nor by heat over production secondary to bioincompatibility reactions. Consequently, haemodynamic responses to dialytic ultrafiltration may be regarded as the main regulatory factor of thermal balance.

Aged↗

PubMedDate not supplied

[The hemodiafiltration with infusion of acetate-free dialysis fluid can modify the inflammatory response in patients "high responders" to inflammatory stimuli?].

PURPOSE: This study aimed to verify the effects of paired hemodiafiltration on-line (PHF-AF) on inflammation in patients who were "high responders" to inflammatory stimuli: elevated C-reactive protein (CRP), genetic polymorphisms influencing a low transcription for interleukin-10 (IL-10) and a high transcription for IFN-gamma. METHODS: Ten patients selected as high responders for IFN-gamma and low responders for IL-10 were included in a crossover study to compare PHF-AF and standard bicarbonate hemodialysis (BHD). At study entry and before the start of each dialysis session the following examinations were performed: CRP, albumin, fibrinogen, ferritin, transferrin, prealbumin and serum levels of IL-6, IL-10, IFN-gamma, tumor necrosis factor-alpha (TNF-alpha). After the 1st and 3rd week of the study, the blood samples were also collected after the dialysis session. RESULTS: . There was a significant reduction in albumin and prealbumin in PHF-AF patients during the study; none of the other parameters were changed in both patient groups. CRP tended to be elevated after dialysis in both PHF-AF and BHD. While IL-6, IL-10 and IFN-gamma were unchanged during the dialysis session, there was a significant variation in TNF-alpha levels, which were increased in BHD (from 10.9 +/- 3.1 to 14.7 +/- 4.1 pg/mL; p=0.004) and reduced in PHF-AF (from 11.9 +/-2.8 to 6.3 +/- 2.2 pg/mL; p=0.0004). CONCLUSION: Although the cytokine levels were unchanged during the study in both BHD and PHF-AF, the modification of TNF-alpha during the dialysis session was considered as inflammatory significance.

Acetates↗

PubMedDate not supplied

Humoral immune response and natural killer activity in patients with mixed cryoglobulinemia.

OBJECTIVE: Based on serological and molecular evidence of hepatitis C virus (HCV) infection in a significant proportion of patients with mixed cryoglobulinemia (MC), a direct association between HCV and MC has been suggested. The goal of the present study was to investigate the role played by HCV and by the immune response to the virus in the pathogenesis of mixed cryoglobulinemia. METHODS: A competitive reverse transcription polymerase chain reaction was employed to evaluate the concentrations of specific HCV RNA sequences in different clinical specimens (plasma, sera, cryoprecipitates, bone marrow and peripheral blood cells). Using recombinant and synthetic peptides covering the HCV core, envelope 1 (E1) and nonstructural regions 4 (NS4) and 5 (NS5), the humoral immune response in a group of MC patients was assessed with an enzyme-linked immunosorbent assay. Natural killer (NK) cell activity was estimated using a 4 hr 51 Cr release assay. RESULTS: Quantitation of the RNA molecules in the biological samples confirmed an increased virion concentration in cryoprecipitates from 13/15 patients with mixed cryoglobulinemia. Analysis of the humoral immune response against the synthetic peptides suggested a distinct response to HCV antigens in MC patients when compared to patients with HCV infection but without serological evidence of cryoglobulinemia. Unstimulated NK cell functioning was below the normal range in all patients tested. However, peripheral blood mononuclear cells showed no enhancement of NK activity by the interferon inducer polyinosinic acid:polycytidilic acid. Enhancement by interferon-alpha was normal, suggesting an impairment in interferon production. CONCLUSION: The quantitative data are in line with the hypothesis of a direct or indirect role of HCV in mixed cryoglobulinemia. The abnormal immune response could be involved in the onset and persistence of HCV infection, and possibly in the appearance of cryoglobulinemia.

Antibody Formation↗

PubMedDate not supplied

Familial membranous nephropathy.

Numerous HLA studies suggest that genetic factors play an important role in the development of membranous nephropathy (MN). We studied seven patients with idiopathic MN, from three unrelated families of Italian ancestry. Complement phenotype analysis and restriction fragment length polymorphism (RFLP) typing of HLA class II and of the switch region genes were done in family members. In the first family, the father, one son, and one daughter had MN; another daughter had clinical glomerulonephritis. The three members with MN shared one HLA haplotype carrying DR beta 11; in the two siblings with the disease, the second HLA haplotype carried the DR beta 3.2 allele. In families 2 and 3, two brothers had MN: in family 2, they differed in at least one haplotype; in family 3, they differed in both haplotypes. Only family 3 was informative with regard to the RFLP of the switch region genes: the two siblings were identical for both Ig heavy chain haplotypes. No clinical, laboratory or morphologic features consistent with a secondary form of the disease were found. Familial clustering of MN suggests a genetically transmitted mechanism.

Adult↗