Abstract Comparative analysis of the different subsets of CD4+ T-lymphocytes may provide hints on the immunologic mechanisms operating in the long-term fate of a kidney transplant. We analyzed ...peripheral regulatory CD4+ T cells (Tregs) and CD4+ cytotoxic T lymphocytes (CTLs) in antibody-mediated chronic rejection (AMCR), in middle-term kidney transplants (2–4 years, MTKT) with good graft function and rejection-free history, in long-term kidney transplants (> 15 years, LTKT) and in normal healthy subjects (NHS). Transplant groups with good prognosis (MTKT and LTKT) displayed a significant lower amount of CD4+ CD25high T lymphocytes than NHS, with a trend of a higher percentage in AMCR than in MTKT and LTKT. However, CD4+ CD25high Foxp3+ cells were significantly higher in LTKT and MTKT than AMCR. Characterization of CD4+ CD25high T cells showed a marked increase of intracellular CTLA-4 in the AMCR group in respect to the other transplant groups, while the expression of the surface molecule seemed to follow a reverse trend. In addition, CD27, a costimulatory receptor involved in long-term T cell survival and prevention of immune tolerance, is significantly reduced in CD4+ CD25high and CD4+ Foxp3+ T cells in the LTKT in respect to the other transplant groups. CD4+ CD25high CD45RO+ and CD4+ Foxp3+ CD45RO+ regulatory T cells with memory function were increased in LTKT compared to NHS and for the latter also in AMCR group. Finally, CD4+ CTLs that were quantified on the basis of granzyme A expression, were more represented in AMCR patients in comparison to the other groups. Strikingly, CD27 in the CD4+ CTLs was suppressed in LTKT and MTKT and markedly expressed in AMCR group. No significant differences in the expression of CD28 were observed among different groups. In conclusion, different profiles of Tregs and CD4+ CTL populations correlate with different long-term conditions of kidney-transplanted patients, suggesting their role in the development of immunologic events in kidney transplantation.
Pneumotoxic drugs like amiodarone and m-TOR inhibitors (m-TORi) may be administered contemporaneously in therapy for patients who had renal transplants. We present a case of amiodarone pulmonary ...toxicity (APT) in a patient treated with amiodarone and everolimus. A 57-year-old Caucasian male, under treatment with both everolimus (for 3 years) and amiodarone (for 2 months), presented with fever, dyspnoea and a negative chest X-ray after his second kidney transplant with suboptimal serum creatinine (3 mg/dl). A non-contrastive high-resolution CT scan showed bilateral interstitial lung disease with an associated reduction in carbon monoxide diffusing capacity. Bronchoalveolar lavage (BAL) was negative for an infection, but BAL cytology was suitable for APT (50% of ‘foamy' macrophages). A complete recovery was achieved after amiodarone interruption and an oral steroid therapy increase. Everolimus was continued. His kidney function remained unchanged in the upcoming months. In conclusion, we suggest a possible synergistic effect between m-TORi and amiodarone. Furthermore, we propose a diagnostic algorithm that can be used as a surveillance tool to identify a potential initial lung damage in patients treated with 1 or more pneumotoxic drugs.
About ten years ago it was discovered that changes in filter design which increase passive filtration improved dialysis efficiency. Later, these modified membranes showed similar intra-dialytic ...efficiency when used in on-line hemodiafiltration or in bicarbonate dialysis, called internal hemodiafiltration.
On the basis of these previous results, we studied the long-term effects of internal hemodiafiltration, in comparison with low-flux bicarbonate dialysis. The pre-dialysis beta2-microglobulin level was chosen as the primary outcome variable. A prospective multicenter study with a cross-over scheme, 2 treatments and 3 periods, was designed. Twenty-four patients, followed in two dialysis centers, were enrolled. Many other parameters were measured every month at the first dialysis session of the week. The intra-dialytic removal of urea, beta2-microglobulin and homocysteine was also calculated.
The removal of uremic toxins was significantly higher in internal hemodiafiltration than in low-flux bicarbonate dialysis. The pre-dialysis value of urea, phosphorus, beta2-microglobulin and homocysteine was lower during internal hemodiafiltration as compared with low-flux bicarbonate dialysis. The mean pre-dialysis value of hemoglobin was significantly higher during internal hemodiafiltration than low-flux bicarbonate dialysis, with a trend towards a significantly lower consumption of erythropoiesis stimulating agents during internal hemodiafiltration as compared with low-flux bicarbonate dialysis.
Long-term treatment with internal hemodiafiltration improves the removal of small molecules and stops the continuous increase of middle molecules as seen in low-flux bicarbonate dialysis. Internal hemodiafiltration may substitute low-flux bicarbonate dialysis, but we need new prospective studies about long-term hard end-points.
Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) is a rare and recently identified disease with a poor prognosis irrespective of the treatment. Recently, the possibility of ...recurrent or de novo PGNMID after kidney transplantation has been reported, which is associated with a better prognosis compared to PGNMID on native kidneys. Nevertheless, at present, due to the very few cases of recurrent PGNMID diagnosed, there is no proven effective treatment. Here, we report a case of recurrent PGNMID successfully treated with plasmapheresis, steroids and mycophenolate mofetil. Our report suggests that plasmapheresis might be a valid therapeutic option to treat recurrent PGNMID.
Background Delayed graft function (DGF) is an early complication of kidney transplantation (KT) associated with increased risk of early loss of graft function. DGF increases using kidneys from ...extended criteria donors (ECD). NGAL is a 25KDa protein proposed as biomarker of acute kidney injury. The aim of this study was to investigate the role of NGAL as an early and accurate indicator of DGF and Tacrolimus (Tac) toxicity and as a mediator of tissue regeneration in KT from ECD. Methods We evaluated plasma levels of NGAL in 50 KT patients from ECD in the first 4 days after surgery or after Tac introduction. Results Plasma levels of NGAL at day 1 were significantly higher in DGF group. In the non DGF group, NGAL discriminated between slow or immediate graft function and decreased more rapidly than serum creatinine. NGAL increased after Tac introduction, suggesting a role as marker of drug toxicity. In vitro, hypoxia and Tac induced NGAL release from tubular epithelial cells (TEC) favoring an autocrine loop that sustains proliferation and inhibits apoptosis (decrease of caspases and Bax/Bcl-2 ratio). Conclusions NGAL is an early and accurate biomarker of graft function in KT from ECD favoring TEC regeneration after ischemic and nephrotoxic injury.
Summary
A 50‐year old female was treated with anidulafungin after fluconazole treatment, for a complex clinical picture and immunosuppression. Anidulafungin was chosen when liver function test was ...abnormal in a setting of multiple causes of liver toxicity.
Hemodialysis prevents liver disease caused by hepatitis C virus: Role of hepatocyte growth factor.
Hemodialysis increases markedly the serum levels of hepatocyte growth factor (HGF) so that regular ...dialysis treatment (RDT) mimics the regular administration of HGF as a drug. Therefore, we have studied the effects of dialysis-associated HGF production on the severity of liver damage caused by hepatitis C virus (HCV).
Biochemical tests of liver function and liver biopsy were performed in 10 patients on RDT and in 11 patients without renal disease (WRD) converted to anti-HCV serum-positive test for the same time (48 ± 4 months). The HGF serum concentration was measured by enzyme immunoassay. In patients on RDT, HGF was measured just before starting a dialysis session (T0), at 15 and 240 minutes of dialysis (T15 and T240), and 24 hours later (T24hr).
Serum HGF was similar in WRD (average 0.17 ng/ml) as in RDT at T0 (0.25 ng/ml). In RDT serum HGF increased markedly at T15 and T240 (5.51 and 2.67 ng/ml, respectively, P < 0.001 vs. WRD and T0) and was still higher than baseline at T24hr (0.41 ng/ml, P < 0.05). Both grade of necroinflammatory activity and stage of fibrosis were significantly lower in RDT than in WRD (both, P < 0.001). The number of apoptotic hepatocytes was also significantly reduced in patients on RDT compared with patients WRD.
These results show that HCV-related liver disease is more benign in patients on RDT. The phenomenon may depend on the marked and prolonged HGF release caused by dialysis.
Abstract Background Peroxisome Proliferator-Activated Receptor γ (PPARγ) is a nuclear receptor that regulates the transcription of genes associated with lipid and glucose metabolism. Recently, it has ...been shown that PPARγ modulates the activity of T cells, resulting in inhibition of T cell proliferation and IL-2 release. In this study we investigated whether the PPARγ ligand rosiglitazone (R) enhances in vitro the immunosuppressive effects of cyclosporine A (CsA). Methods CD4+ T cells isolated from peripheral blood mononuclear cells of healthy donors were activated either with mitogens or by one-way mixed lymphocyte reaction. The activated T cells were treated with (1) CsA at low and high concentration (50, 150 ng/ml); (2) R (20 μM); (3) R (20 μM) in combination with CsA at low concentration (50 ng/ml). We studied the effects of the various treatments on cell proliferation (incorporation of 3 H thymidine), the cell-cycle phases (FACS analysis), IL-2 release (ELISA), and IL-2 receptor (CD25) expression (FACS analysis). Results R used alone reduced T cell proliferation and CD25 expression. Low-dose CsA combined with R was significantly more powerful than either high-dose CsA alone or R alone in suppressing IL-2 release, arresting the T cell cycle, and blocking the growth of activated T cells. Conclusion PPARγ ligand R potentiates in vitro the inhibitory action of CsA on activated T helper cells. The combined use of PPARγ ligands and low-dose CsA represents a rationale therapeutic approach aimed to prevent CsA nephrotoxicity while maintaining adequate immunosuppression.
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