Toll-Like Receptor 3 mRNA Expression of Peripheral Blood Mononuclear Cells Identifies Kidney Recipients with Potential for Improved Graft Performance.

BACKGROUND Toll-like receptor 3 expression is detected both on the cell membrane and in endosomes of peripheral blood mononuclear cells (PBMC). Our goal in this study was to determine to what extent a single, baseline measurement of non-stimulated PBMC TLR3-mRNA can be related to baseline GFR (b-GFR) and post-follow-up-GFR (F-up-GFR) of a kidney transplant (KT) and baseline immunosuppression. MATERIAL AND METHODS In non-stimulated PBMC we investigated averaged mRNA expression of Toll-like receptor 3. A total of 133 patients were enrolled; the median of months after KT surgery was 11.4, with median F-up at 21.3 months. A favorable course (FCF) was determined if F-up-eGFR improved. An unfavorable course (UCF) was determined if F-up-eGFR was lower at the end of the observation. RESULTS The highest TLR3-mRNA expression was at b-GFR grade 3b; it was moderately higher at b-GFR grade 3a, and marginally higher at b-GFR grades 1+2. Most of the FCF group had b-GFR grade 3b, less frequent obesity, more effective immunosuppression, and much higher TLR3-mRNA (59% of cases were in the high-TLR3 area). Both delayed graft function (DGF) and TLR3-mRNA range below the median for the entire KT cohort (low-TLR3 area) had a negative association with b-GFR. The UCF group had more frequent DGFs and obesity, less effective immunosuppression, and lower TLR3-mRNA. CONCLUSIONS In patients with GFR grade 3, high levels of TLR3-mRNA are associated with improved graft efficacy. In patients with impaired graft function, low TLR3- mRNA expression reduces the likelihood of improved renal graft function.

Toll-like 4 receptor (TLR4) expression on peripheral blood mononuclear cells in renal transplant recipients with pre-transplant chronic interstitial nephritis indicates patients at risk of graft deterioration.

Data binding the expression of Toll-like 4 receptor (TLR4ex), transplanted kidney function, and the cause of pre-transplant end-stage renal disease are scarcely available. OBJECTIVE: To investigate the relationship between pre-transplant chronic interstitial nephritis (CIN), TLR4ex and transplanted kidney function. MATERIALS AND METHODS: TLR4ex was measured in peripheral blood mononuclear cells of 43 CIN kidney transplant recipients. We compared TLR4ex among 33 patients with pre-transplant chronic non-infectious interstitial nephritis (NIN) and 10 patients with pre-transplant chronic pyelonephritis (Py). At the beginning (Day-0) TLR4ex, as well as concentrations of cyclosporin A (CyA) and tacrolimus (TAC) were determined. Both CIN and NIN patients were divided according to the respective median of TLR4ex into groups of low-TLR4 expression (L-TLR4ex) and high-TLR4 expression (H-TLR4ex). Serum creatinine/glomerular filtration rate (sCr/EGFR) was assessed on Day-0 and after the follow-up (F-up). The magnitudes of sCr/EGFR change (ΔsCr/ΔEGFR) were evaluated. The treatment was maintained stable along the F-up period (median 11.9 months). RESULTS: Day-0: in CIN with L-TLR4ex TAC was lower but sCr/EGFR were not different from H-TLR4ex; in Py TLR4ex and TAC were lower than in NIN with no difference in sCR/eGFR. After F-up: in CIN with L-TLR4ex sCR/EGFR and ΔsCr/ΔEGFR were worse than in H-TLR4ex; in Py sCR/EGFR and ΔsCr/ΔEGFR were worse than in NIN. The regression analysis points out prospective impact of Py and TLR4ex on sCR/eGFR and ΔsCr/ΔeGFR. CONCLUSION: In CIN, both TLR4ex and Tac appear to be a useful positive predictor of the effectiveness of immunosuppression. Chronic pyelonephritis indirectly promotes faster progression of chronic transplanted kidney disease.

Toll-Like 4 Receptor Expression on Peripheral Blood Mononuclear Cells in Renal Transplant Recipients Can Help to Indicate the Risk of Graft Deterioration in Patients Who Experienced an Episode of Symptomatic Cytomegalovirus Infection.

Data binding the expression of Toll-like 4 receptor (TLR4), transplanted kidney (KT) function, and symptomatic CMV infection (CMV+) are scarcely available. OBJECTIVE: To investigate the relationship between TLR4 expression (TLR4ex) in patients who had a relapse of CMV and transplant function. MATERIALS AND METHODS: TLR4ex was measured in peripheral blood mononuclear cells of KT recipients. We compared TLR4ex among 30 CMV+ patients and 87 patients without CMV infection (CMVneg). At the beginning (day 0) TLR4ex, as well as concentrations of cyclosporin A and tacrolimus were determined. All patients, CMV+ and CMVneg patients were divided according to the respective median of TLR4ex into groups of low-TLR4 expression (L-TLR4ex) and high-TLR4 expression (H-TLR4ex). Estimated glomerular filtration rate (EGFR) was assessed on day 0 and after the follow-up (F-up). The magnitudes of EGFR change (ΔEGFR) were evaluated. Stable treatment along the F-up period (median 11.9 months) was applied. RESULTS: TLR4ex of CMV+ in 67% was below median for all patients. For day 0, in CMV+: no link of TLR4ex with EGFR was found; TLR4ex was lower but day 0 EGFR did not differ from H-TLR4ex. In CMVneg, a GFR-TLR4ex link was present. Post F-up. In CMV+ with L-TLR4ex, EGFR declined, with no change in H-TLR4ex. In CMVneg with H-TLR4ex, EGFR increased, with no change in L-TLR4ex. Both regression and receiver operating characteristic curve analyses points out the impact of CMV+ and TLR4ex on eGFR and ΔEGFR. CONCLUSION: In CMV+, low TLR4ex increases the risk of EGFR deterioration. In CMVneg, high TLR4ex raises the chance of EGFR improvement.

Can the Toll-like receptors 4 expression in peripheral blood mononuclear cells help assess the effectiveness of immunosuppression and the chance of a future good renal transplant function?

BACKGROUND: A small percentage of peripheral blood mononuclear cells (PBMCs) circulating during the kidney transplantation (KT) period remain in the blood long after transplantation. A part of the PBMCs penetrates the graft. AIM: To examine if the choice of immunosuppression may change TLR4ex and how TLR4ex affects the transplant function in the future. MATERIAL: The study population-143 transplanted patients (pts) (55 females, 88 males), mean age on recruitment day 50.33 ±â€¯12.8 years old, mean BMI 25.04 ±â€¯4.18. 41 pts. experienced delayed graft function (DGF+). 55 pts. were treated with cyclosporine A (CsA) and 88 with tacrolimus (Tac). All were treated with mofetil mycophenolate (MMF). The PBMCs acquisition and starting point of the follow-up (TLR-day) was at least one month after KT. METHOD: We investigated averaged mRNA expression of Toll-like receptors 4 (TLR4ex) in non-stimulated peripheral blood mononuclear cells with the use of real-time polymerase chain reaction. The KT pts. (All, Tac, CsA, DGF+) were divided by the respective median of their TLR4ex (lower: L-TLR4ex, higher: H-TLR4ex). Main clinical parameters and transplant biopsy files (if available) were assessed on TLR-day and post follow-up. RESULTS: We found that TLR4ex was reduced for a long time in patients who experienced delayed graft function. L-TLR4ex had a higher proportion of DGF+ patients, and patients treated with CsA but lower of those treated with Tac than in H-TLR4ex. The amplitude of changes in renal function parameters (ΔEGFR%/ΔsCr/ΔsCr%) was clearly less favorable for L-TLR4ex. Tacrolimus expressed a stabilizing effect. Both the positive vasculitis score and chronic graft nephropathy were more frequent in the L-TLR4ex group. On TLR-day an association of renal function and Tac concentration with TLR4ex was clear only in the tacrolimus population. The TLR4ex was lower in patients with a future deterioration of the graft function. CONCLUSION: In kidney transplant recipients the occurrence of DGF results in a long-term reduction of the averaged TLR4ex in PBMC. Tacrolimus exerts a clear, stabilizing, positive and dose-dependent effect on TLR4ex. An improvement in renal transplant function may be expected in KT patients with high TLR4ex. Evaluation of the averaged TLR4ex can be used to assess the efficacy of immunosuppression in the treatment with tacrolimus and to estimate the likelihood of deterioration in renal function.

Urinary myeloid IgA Fc alpha receptor (CD89) and transglutaminase-2 as new biomarkers for active IgA nephropathy and henoch-Schönlein purpura nephritis.

BACKGROUND: IgA nephropathy (IgAN) and Henoch-Schönlein purpura nephritis (HSPN) are glomerular diseases that share a common and central pathogenic mechanism. The formation of immune complexes containing IgA1, myeloid IgA Fc alpha receptor (FcαRI/CD89) and transglutaminase-2 (TG2) is observed in both conditions. Therefore, urinary CD89 and TG2 could be potential biomarkers to identify active IgAN/HSPN. METHODS: In this multicenter study, 160 patients with IgAN or HSPN were enrolled. Urinary concentrations of CD89 and TG2, as well as some other biochemical parameters, were measured. RESULTS: Urinary CD89 and TG2 were lower in patients with active IgAN/HSPN compared to IgAN/HSPN patients in complete remission (P < 0.001). The CD89xTG2 formula had a high ability to discriminate active from inactive IgAN/HSPN in both situations: CD89xTG2/proteinuria ratio (AUC: 0.84, P < 0.001, sensitivity: 76%, specificity: 74%) and CD89xTG2/urinary creatinine ratio (AUC: 0.82, P < 0.001, sensitivity: 75%, specificity: 74%). Significant correlations between urinary CD89 and TG2 (r = 0.711, P < 0.001), proteinuria and urinary CD89 (r = - 0.585, P < 0.001), and proteinuria and urinary TG2 (r = - 0.620, P < 0.001) were observed. CONCLUSIONS: Determination of CD89 and TG2 in urine samples can be useful to identify patients with active IgAN/HSPN.

Reccurence of Kaposi's sarcoma after increased exposure to sirolimus.

UNLABELLED: The conversion to sirolimus treatment is recently indicated as an effective therapy of Kaposi's sarcoma (KS) in transplant patients. We present two treatment modalities in patients with KS and recurrence of the disease after increasing sirolimus dose. Among 1034 renal transplants performed at our center, three (0.3%) suffered from KS. Initial immunosuppression consisted of cyclosporine, azathioprine and prednisone in one patient; and tacrolimus, mycophenolate mofetil and prednisone in two patients. KS symptoms appeared within one year post-transplantation. Two patients developed cutaneous tumor; one disseminated disease, including the skin, mediastinal lymph nodes and both lungs. After histological confirmation of KS immunosuppression was minimized: Two were converted to sirolimus (1-2 mg/day, level 5-8 ng/ml) treatment; the third patient discontinued tacrolimus and was administered 1 g/day mycophenolate mofetil. Gradual regression of KS was observed in all the patients. In one patient, 8 months after regression of lung KS, the dose of sirolimus was increased to 2 mg/day (level raised to 13.8 ng/ml). Recurrent disease developed afterwards involving diffuse interstitial infiltrates with nodular changes in both lungs. For the second time the dose of sirolimus was reduced to 1 mg/day (level 4-5 ng/ml) and lung lesions regressed 5 months later. Renal function was stable (creatinine 1.3-1.9 mg/dl) in all patients, 24 months from KS onset. IN CONCLUSION: treatment by low sirolimus or mycophenolate mofetil doses caused regression of KS. Recurrence of KS after increasing sirolimus dose suggests that regression of KS is a result of diminished immunosuppression, not the direct antineoplastic effect of sirolimus. Careful maintenance of low sirolimus levels is suggested.

Kaposi's sarcoma in renal transplant recipients.

Kaposi's sarcoma (KS) is a spindle-shaped vascular cell tumor that occurs in the skin, lymphoid, respiratory and gastrointestinal tissues. It may resemble aggressive malignant neoplasm in HIV-related or in post-transplant types but classic form may behave as benign, potentially controllable and reversible hyperplasia. KS lesions from the onset are dispersed and multicentric. KS probability increases in solid organ transplant recipients (approximately 3/1000 patients). KS occurrence is associated with: type and dose of immunosuppression, chronic stimulation by foreign allograft antigens, viral infections (Herpes virus 8), anti rejection and induction therapy, etc. 90% of KS cases appear as dark blue or purplish macular lesions that may form nodular tumors. Histological picture shows networks of spindle shaped cells and vascular spaces surrounded by an endothelial cell layer. There is no uniform schema of KS treatment in renal transplant recipients. Immunosuppression must be reduced to the lowest levels which preserve allograft function. CsA should be converted to mofetil mycophenolate or mTOR-inhibitors. After conversion to MMF regression of KS was observed, although low therapeutic MMF doses seem to be appropriate. Sirolimus seems to inhibit the growth of established vascularized tumors and this effect is best realized with relatively low immunosuppressive doses of drug.

[Serum apolipoproteins A1, B and Apo A1/Apo B index in children with advanced chronic renal failure and on dialysis]. / Apolipoproteiny A1 i B i wskaznik ApoA1/ApoB u dzieci z zaawansowana przewlekla niewydolnoscia nerek i leczonych nerkozastepczo.

UNLABELLED: There is an increased risk of atherogenesis in adult patients with chronic renal failure (CRF). The aim of study was estimation of the risk of atherogenesis in children with advanced CRF and in children receiving renal replacement therapy. To evaluate the risk ApoA1 and ApoB concentrations were measured and ApoA1/ApoB index was calculated. RESULTS: Increased ApoA1 concentration was found in CADO group without any marked change in other groups. The relative capacity of protein part (ApoA1) of HDL seems to increase in both HD and CAPD children. But in case of ApoB (LDL) the same increase was observed only in HD children. The available data suggest that increased protein capacities of LDL and HDL are connected with lower diameter and modified properties (atherogenic potential) of those molecules. Normal ratio of ApoB/LDL in CAPD group is counterbalanced with increased serum concentration of LDL. A positive correlation between ApoA1/ApoB index value and total protein concentration that has been found in HD group suggests a role of several factors connected with dialysis regimen that affect nutrition status of HD patients. ApoA1/ApoB shows only medium level correlation with other classic indices based on total cholesterol, HDL and LDL concentrations. CONCLUSION: The change of HDL and LDL concentration in children receiving renal replacement therapy failed to significantly affect ApoA1/ApoB index. This fact excluded the possibility to apply ApoA1/ApoB as a tool that could point out the better type of treatment. Taking together the available data describing the relation between protein capacity and size of lipoprotein molecules and our calculations, we suppose that CAPD is connected with slightly lower risk of atherogenesis than HD.