Impaired erythropoietin production in liver transplant recipients: the role of calcineurin inhibitors.

Anemia is common following liver transplantation. Because cyclosporine inhibits erythropoietin (Epo) production in experimental models, we investigated whether Epo production was impaired in liver transplant recipients receiving a cyclosporine- or tacrolimus-based immunosuppressive regimen. First, serum Epo levels were measured before and 1 year after transplantation in 35 liver transplant recipients. Second, serum Epo levels were compared in a large series of liver transplant recipients with stable graft and renal functions: 27 receiving a cyclosporine-based and 31 receiving a tacrolimus-based immunosuppressive regimen. A reference group was made up of 22 blood donors and 21 nontransplanted subjects with iron-deficiency anemia. Serum Epo levels were significantly lower after than before liver transplantation, especially in cyclosporine-treated patients. Serum Epo concentrations correlated with hematocrit values in both transplant recipients and control subjects. Using multiple linear regression models, the polynomial relationship between hematocrit and serum Epo values was similar to the control group in patients under tacrolimus, whereas Epo production was significantly reduced in patients under cyclosporine-based immunosuppression. Hematocrit values and the type of calcineurin inhibitor were the only parameters independently related to Epo levels. In conclusion, cyclosporine, but not tacrolimus, inhibits Epo production at the doses used in clinical practice.     

Delivery of erythropoietin by encapsulated myoblasts in a genetic model of severe anemia

BACKGROUND: Existing animal models of anemia inadequately reflect the hematocrit usually present in chronic renal failure (CRF) patients and do not permit long-term treatment studies. The transgenic mouse strain 134.3LC (Epo-TAg(H)) displays a severe chronic anemia resembling that observed clinically during CRF, while displaying an active, normal life span. This phenotype makes it a particularly interesting mouse model for testing erythropoietin (Epo)-based gene transfer strategies. METHODS: Ex vivo gene therapy was employed to administer mouse Epo to homozygous anemic Epo-TAg(H) mice. Encapsulated C(2)C(12) myoblasts genetically engineered to secrete 163 IU mouse Epo/10(6) cells/day were subcutaneously transplanted on the dorsal flank of the mice. Efficacy of delivered Epo was monitored by weekly measurements of animal hematocrit. RESULTS: Most treated homozygous Epo-TAg(H) mice displayed only a transient rise in hematocrit before eventually decreasing to levels as low as 3%. Administering the immunosuppressor anti-CD4+ monoclonal antibody (mAb) to homozygous Epo-TAg(H) mice, beginning at the time of implantation, permitted a rise in hematocrit that remained stable at elevated levels in cases of continued immunosuppression. CONCLUSIONS: Mice having the T antigen insertion in both Epo alleles appeared to develop an immune response to the natural mouse Epo delivered by encapsulated cells. By preventing this reaction using immunosuppression, we demonstrate that encapsulated myoblasts can deliver therapeutic doses of mouse Epo systemically and restore hemopoiesis in a genetic model of severe anemia.     

Erythropoietin delivery by genetically engineered bone marrow stromal cells for correction of anemia in mice with chronic renal failure

The goal of this research was to develop a strategy to couple stem cell and gene therapy for in vivo delivery of erythropoietin (Epo) for treatment of anemia of ESRD. It was shown previously that autologous bone marrow stromal cells (MSCs) can be genetically engineered to secrete pharmacologic amounts of Epo in normal mice. Therefore, whether anemia in mice with mild to moderate chronic renal failure (CRF) can be improved with Epo gene-modified MSCs (Epo+MSCs) within a subcutaneous implant was examined. A cohort of C57BL/6 mice were rendered anemic by right kidney electrocoagulation and left nephrectomy. In these CRF mice, the hematocrit (Hct) dropped from a prenephrectomy baseline of approximately 55% to 40% after induction of renal failure. MSCs from C57BL/6 donor mice were genetically engineered to secrete murine Epo at a rate of 3 to 4 units of Epo/10(6) cells per 24 h, embedded in a collagen-based matrix, and implanted subcutaneously in anemic CRF mice. It was observed that Hct increased after administration of Epo+MSCs, according to cell dose. Implants of 3 million Epo+MSCs per mouse had no effect on Hct, whereas 10 million led to a supraphysiologic effect. The Hct of CRF mice that received 4.5 or 7.5 million Epo+MSCs rose to a peak 54+/-4.0 or 63+/-5.5%, respectively, at 3 wk after implantation and remained above 48 or 54% for >19 wk. Moreover, mice that had CRF and received Epo+MSCs showed significantly greater swimming exercise capacity. In conclusion, these results demonstrate that subcutaneous implantation of Epo-secreting genetically engineered MSCs can correct anemia that occurs in a murine model of CRF.     

Kidney and anemia in familial amyloidosis type I

BACKGROUND: Familial amyloid polyneuropathy (FAP) type I is caused by a mutated transthyretin (TTR V30M) and characterized by a sensorimotor and autonomic neuropathy. Renal, cardiac, and ocular abnormalities can also occur. Anemia has been described in previous reports, but its prevalence in Portuguese FAP patients is not precisely known. The aim of this study was to estimate the prevalence of anemia in FAP type I Portuguese patients and to evaluate the contribution of erythropoietin (Epo) to its genesis. METHODS: A retrospective cross-sectional study was undertaken to determinate the prevalence and characteristics of anemia in 165 FAP patients. For comparison analysis, 3 control groups were also evaluated, 1 group of 46 apparently healthy subjects, 1 group of 17 asymptomatic carriers of FAP-trait, and a group of 14 non-FAP patients with chronic renal insufficiency. Serum Epo levels were analyzed in all groups. RESULTS: Anemia was present in 24.8% of symptomatic FAP patients. Iron stores, B12 vitamin, and serum folate levels were normal. FAP patients presented significantly lower serum Epo levels than healthy controls (P= 0.003). Epo levels were found lower than expected for the degree of anemia and in 17.5% were undetectable. Low Epo values were observed independently of the presence of renal failure or anemia, and sometimes preceded clinical disease. CONCLUSION: Anemia in FAP type I is a common manifestation. The results clearly suggest a defective endogenous Epo production in the genesis of the anemia.     

Tubulovascular Cross-Talk by Vascular Endothelial Growth Factor A Maintains Peritubular Microvasculature in Kidney

Vascular endothelial growth factor A (VEGFA) production by podocytes is critical for glomerular endothelial health. VEGFA is also expressed in tubular epithelial cells in kidney; however, its physiologic role in the tubule has not been established. Using targeted transgenic mouse models, we found that Vegfa is expressed by specific epithelial cells along the nephron, whereas expression of its receptor (Kdr/Vegfr2) is largely restricted to adjacent peritubular capillaries. Embryonic deletion of tubular Vegfa did not affect systemic Vegfa levels, whereas renal Vegfa abundance was markedly decreased. Excision of Vegfa from renal tubules resulted in the formation of a smaller kidney, with a striking reduction in the density of peritubular capillaries. Consequently, elimination of tubular Vegfa caused pronounced polycythemia because of increased renal erythropoietin (Epo) production. Reducing hematocrit to normal levels in tubular Vegfa–deficient mice resulted in a markedly augmented renal Epo production, comparable with that observed in anemic wild-type mice. Here, we show that tubulovascular cross-talk by Vegfa is essential for maintenance of peritubular capillary networks in kidney. Disruption of this communication leads to increased renal Epo production and resulting polycythemia, presumably to counterbalance microvascular losses.     

Effects of erythropoietin-gene electrotransfer in rats with adenine-induced renal failure

BACKGROUND: We previously demonstrated that erythropoietin (Epo) expression increases in five-sixths nephrectomized rats, after muscle-targeted gene transfer by in vivo electroporation, using plasmid DNA expressing rat Epo (pCAGGS-Epo). Here, we apply this method to a rat model with severe anemia associated with chronic renal failure; these rats have hematocrit levels in the 30-35% range, similar to those in humans with end-stage renal disease. METHODS: Wistar rats were treated to produce adenine-induced uremia. The uremic rats were then treated with muscle-targeted gene transfer using pCAGGS-Epo. Some uremic rats died from chronic renal failure; one of these was dissected, and the kidneys were histologically examined. For the remaining rats, we measured body weight and blood pressure, and obtained blood samples regularly. RESULTS: The uremic rats showed severe anemia, with hematocrit levels at 32.6 +/- 3.3%. Epo-gene transfer increased Epo expression and serum Epo levels, and also increased the hematocrit levels to 64.5 +/- 4.8%. The dose of pCAGGS-Epo used in this study did not induce severe hypertension. CONCLUSIONS: Continuous Epo-gene expression improves the anemia associated with chronic renal failure, and without severe side effects. Our results support the potential use of gene electrotransfer for human gene therapy applications.     

Nephritogenic cytokines and disease in MRL-Fas(lpr) kidneys are dependent on multiple T-cell subsets

BACKGROUND: Renal parenchymal cells produce cytokines, colony-stimulating factor-1 (CSF-1), granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-alpha (TNF-alpha), which recruit autoreactive T cells and, in turn, elicit renal injury in MRL-Fas(lpr) mice. METHODS: To determine whether select T-cell populations regulate intrarenal nephritogenic cytokines (CSF-1, GM-CSF, and TNF-alpha) and renal disease, we compared MRL-Fas(lpr) mice that are genetically deficient in T-cell receptor (TCR) alpha beta T cells, CD4 T cells, and major histocompatibility complex class I (MHC class I), lacking CD8 and double negative (DN) T cells, with wild-type mice. To identify the T cells instrumental in downstream (effector) events, we delivered CSF-1 or GM-CSF into the kidney via gene transfer in these select T-cell-deficient and wild-type strains. RESULTS: Intrarenal CSF-1, GM-CSF, and TNF-alpha were absent or dramatically reduced in TCR alpha beta, CD4, and class I-deficient MRL-Fas(lpr) strains as compared with wild-type mice. In addition, the decrease in CSF-1, GM-CSF, and TNF-alpha was associated with a reduced kidney leukocytic infiltrates and spontaneous autoimmune nephritis. Intrarenal ex vivo retroviral gene transfer of CSF-1 and GM-CSF failed to elicit nephritis in these T-cell-deficient MRL strains (TCR alpha beta, CD4, CD8/DN) as compared with wild-type mice. CONCLUSIONS: Multiple T-cell populations initiate renal disease by increasing intrarenal nephritogenic cytokines, CSF-1, GM-CSF, and TNF-alpha. CSF-1 and GM-CSF recruit additional CD4 and CD8 and DN T cells, which augment downstream events, resulting in progressive autoimmune renal disease. We suggest that MRL-Fas(lpr) kidney disease is driven by a T-cell amplification feedback loop dependent on multiple T-cell populations.     

Erythropoietin-producing renal cell carcinoma in chronic hemodialysis patients: A report of two cases

Erythropoietin (EPO)-producing renal cell carcinomas in two hemodialysis patients are reported. Despite deteriorated kidney function, these patients did not manifest anemia at diagnosis and their elevated serum EPO levels rapidly returned to within the normal range after nephrectomy. Immunohistochemical staining of the resected specimens showed production of erythropoietin in the tumor cells in one case and in the lining cells of the cyst wall in the other case. Renal cell carcinoma could cause an increase of blood hematocrit level in dialysis patients.     

Colony-promoting activity in mice kidneys with phenylhydrazine hemolytic anemia

Aqueous anemic mice kidney extracts (MKE) were assessed colony-promoting activity (CPA) of hematopoietic progenitor cells in serum-free cultures stimulated by interleukin-3 and erythropoietin (Epo). Mice with hemolytic anemia followed by phenylhydorazine (PHZ) injection for 3 days showed a decrease in the hematocrit (25.4%) and an increase in serum Epo by 14-fold of the control on day 3 after the treatment. At 3 days, the total number of hematopoietic progenitor cells in the bone marrow of PHZ mice decreased by 67% of the control, while these cells in the spleen increased to 22-fold of the control on day 3 and 55-fold on day 6. A significant increase in CPA was observed in MKE prepared from PHZ mice kidneys. Additionally, bone marrow suppressive anemia induced by 5-fluorouracil resulted in enhanced CPA the same as for PHZ mice, but in contrast, anemia with suppression of Epo-production due to nephrotoxicity induced by cisplatin caused a decrease in CPA. These results suggest that CPA in MKE correlates with hematopoietic conditions, and may have a definite role in hematopoiesis through the function of the kidney.     

Colony-Promoting Activity in Mice Kidneys with Phenylhydrazine Hemolytic Anemia

Aqueous anemic mice kidney extracts (MKE) were assessed colony-promoting activity (CPA) of hematopoietic progenitor cells in serum-free cultures stimulated bv interleukin-3 and erythropoietin (Epo). Mice with hemolytic anemia followed by phenylhydorazine (PHZ) injection for 3 days showed a decrease in the hematocrit (25.4%) and an increase in serum Epo by 14-fold of the control on day 3 after the treatment. At 3 days, the total number of hematopoietic progenitor cells in the bone marrow of PHZ mice decreased by 67% of the control, while these cells in the spleen increased to 22-fold of the control on day 3 and 55-fold on day 6. A significant increase in CPA was observed in MKE prepared from PHZ mice kidneys. Additionally, bone marrow suppressive anemia induced by 5-fluorouracil resulted in enhanced CPA the same as for PHZ mice, but in contrast, anemia with suppression of Epo-production due to nephrotoxicity induced by cisplatin caused a decrease in CPA. These results suggest that CPA in MKE correlates with hematopoietic conditions, and may have a definite role in hematopoiesis through the function of the kidney.     

Hyperlipidemia aggravates renal disease in B6.ROP Os/+ mice

INTRODUCTION: Reduction of renal mass is frequently associated with progressive loss of kidney function. We examined the effects of hyperlipidemia on renal pathology and mediators of tissue damage in B6.ROP Os/+ mice, a model of reduced renal mass. METHODS: C57BL/6 control mice and B6.ROP Os/+ mice were fed normal rodent chow or a high fat, high cholesterol (HFHC) diet for 12 weeks. Kidney function and renal pathology were assessed. RESULTS: Hyperlipidemia led to a decline in kidney function in C57BL/6 mice. Renal pathology was characterized by an increase in glomerular matrix and cellularity, glomerular and tubulointerstitial macrophage influx, and increased tubular epithelial cell turnover. Chow-fed B6.ROP Os/+ animals demonstrated glomerular hypertrophy with an increase in mesangial matrix and cellularity that was characterized by macrophage influx and increased proliferation. The tubulointerstitium showed increased macrophages as well as tubular atrophy and dilation. Renal pathology was accompanied by an increase in blood urea nitrogen (BUN) and proteinuria. Hyperlipidemia in B6.ROP Os/+ mice resulted in increased plasma BUN compared to chow-fed B6.ROP Os/+ animals and aggravated renal pathology by further increasing glomerular matrix and glomerular hypercellularity. Glomerular hypercellularity was associated with increased expression of platelet-derived growth factor-B (PDGF B) and its receptor beta. Glomerular transforming growth factor-beta (TGF-beta) mRNA expression was increased in B6.ROP Os/+ mice, hyperlipidemic C57BL/6 mice and hyperlipidemic B6.ROP Os/+ animals compared to controls and correlated with the amount of mesangial matrix. CONCLUSION: This study demonstrates that hyperlipidemia worsens renal pathology in B6.ROP Os/+ mice with a decline in renal function mediated at least in part through increased renal expression of the cytokines PDGF B and TGF-beta.     

Profile of cytokine production in mixed kidney lymphocyte culture

Abstract Kidney cells are an important source of immunoregulatory molecules that regulate cell-to-cell interactions, which is the key step in the generation of the immunoresponse to alloantigens. In this study we identified the cytokines that are produced by both lymphoid cells and kidney cells when coincubated in mixed kidney lymphocyte cultures (MKLC). The capacity of kidney cells to stimulate the proliferation of effector allogeneic lymphocytes was assayed by incubating irradiated kidney cells and lymphocyte. The cytokine secretion profile in MKLC was investigated by incubating monolayers of kidney cells with effector peripheral blood mononuclear cells (PBMC). The culture supernatants were harvested on days 1, 2, 3, 4, 5, 6, 7, and 8 and assayed for IL-1β, IL-2, IL-6, and TNF alpha using an ELISA. Kidney cells, in comparison to PBMC stimulator cells were poor stimulators of the allo-proliferation even when HLA expression was increased by IFN gamma treatment. Compared to lymphocyte or kidney cells incubated alone, MKLC induced a considerable stimulation of cytokine production. This increase in cytokine production was observed essentially for IL-2 and IL-6 (at day 3, a 10-fold increase in IL-2 and a 5-fold increase in IL-6). This study provided evidence that target kidney cells and effector lymphocyte interactions generate a number of cytokines such as IL-11, IL-2, IL-6, or TNF alpha. These cytokines are known to modulate alloproliferation and generation of cytotoxic J lymphocytes (CTL).     

Regulatory mechanisms of erythropoietin levels in dialysis patients

We described a radioimmunoassay system for measuring blood erythropoietin (Epo) levels using recombinant human Epo and evaluated the regulatory mechanisms of Epo in dialysis patients. A satisfactory dose-response relationship for Epo levels was observed within the wide range of 3-250 mU/ml with a sensitivity of approximately 5 mU/ml. The Epo levels were found to be 16.1 +/- 8.6 mU/ml (m +/- SD) in 422 uremic patients on maintenance dialysis and 17.1 +/- 7.2 mU/ml in 86 normal subjects. The Epo levels were not statistically different between the two groups, although the hematocrit was significantly lower in the dialysis patients. No correlation was observed between the Epo levels and hematocrit in the dialysis patients. Patients with polycystic kidneys had higher hematocrits and Epo levels than patients with chronic nephritis. No changes in Epo levels were observed with age and with the period of dialysis. Diurnal variations in the Epo levels revealed a significant increase after hemodialysis, and an acute reduction in hematocrit following massive hemorrhage raised the Epo levels up to 3,180 mU/ml. These findings indicate that the Epo levels in dialysis patients are inappropriately low for the severity of anemia and suggest that a negative feedback mechanism of the hematocrit on the Epo secretion may exist in uremic patients as well as in normal subjects and that the threshold for Epo secretion might be 'reset' at a low hematocrit level.     

Oxymatrine inhibits renal fibrosis of obstructive nephropathy by downregulating the TGF-β1-Smad3 pathway

This study investigated whether oxymatrine (OMT) treatment can ameliorate renal interstitial fibrosis in unilateral ureteral obstruction (UUO) mice model. Moreover, the potential mechanisms of such treatment were analyzed. Twenty-four C57/BL6 mice were randomly divided into three groups, namely sham group, vehicle plus unilateral ureteral obstruction (UUO)-treated group, and 100?mg/kg/d OMT plus UUO-treated group. All mice were euthanized seven days after surgery, and their kidneys were harvested. Renal injury, fibrosis, expression of proinflammatory cytokines, and the transforming growth factor-β1/Smads (TGF-β/Smads) and nuclear factor-kappa B (NF-κB)-signaling pathways were assessed. The results showed OMT significantly prevented kidney injury and fibrosis, as evidenced by decreased expression of collagen-1 and fibronectin. Furthermore, OMT administration inhibited the release of inflammatory factors including tumor necrosis factor-α, (TNF-α) interleukin-1β (IL-1β), and interleukin-6 (IL-6), as well as phosphorylated NF-κB p65. In addition, OMT blocked the activation of myofibroblasts by inhibiting the TGF-β/Smad3-signaling pathway. The findings indicate that OMT-attenuated renal fibrosis and inflammation, and this renoprotective effect may be ascribed to the inactivation of the TGF-β/Smad3 and NF-κB p65 pathways.     

Effects of bacillus Calmette-Guèrin and interferon alpha-2B on cytokine production in human bladder cancer cell lines

PURPOSE: To determine the effects of live BCG, autoclaved BCG and interferon alpha-2b on cytokine production in human bladder cancer cell lines. MATERIALS AND METHODS: The release of nine cytokines from the human bladder cancer cell lines, RT4, RT112, SD, MGH and J82, was measured by ELISA assay. The mRNA level of IL-6 and GM-CSF was determined by RT-PCR. RESULTS: BCG and/or interferon alpha-2b differentially increased IL-1beta, IL-6, IL-8, GM-CSF and TNF-alpha production in the bladder cancer cells. High grade cell lines were more responsive to BCG whereas low grade lines were more sensitive to interferon alpha-2b. This correlated with cytotoxicity and growth inhibition induced by these agents. BCG could also induce low levels of IFN-alpha production in all the cell lines. Compared with live BCG, autoclaved BCG had no antiproliferative effect on MGH cells and was less effective in stimulating the production of IL-6, IL-8 and GM-CSF. However, autoclaved BCG was as effective as live BCG in inhibiting growth and stimulating IL-6 and TNF-alpha production of J82 cells. The combination of BCG and interferon alpha-2b also completely suppressed TGF-beta1 production in the MGH and RT112 cell lines. CONCLUSIONS: The combination of BCG and interferon alpha-2b has additive effects in cytokine production from bladder cancer cells. This correlates with cytotoxicity and growth inhibition induced by these agents.     

氩氦刀冷冻消融治疗兔VX2肾癌外周血细胞因子的变化

目的研究冷冻消融治疗兔VX2肿瘤后外周血细胞因子的变化。方法建立兔VX2肾癌模型,将38只荷瘤兔随机分为：冷冻消融组（A组）,根治性肾切除组（B组）,肿瘤对照组（C组）,应用酶联免疫吸附试验法测定治疗前、治疗后21d外周血Th1型细胞因子（IFN-γ、TNF-α和Th2型细胞因子（IL-4、IL-6）浓度的变化。结果治疗后21d组间组内比较显示：冷冻消融组外周血IFN-γ、TNF-α浓度和IFN-γ／／IL-4比值明显升高,IL-6明显降低,与治疗前差异存在统计学意义（P〈0．05）,IL-4与治疗前相比差异无统计学意义（P〉0．05）;冷冻消融组外周血IFN-γ／、IL-4、IL-6浓度和IFN-γ／IL-4比值与肿瘤对照组相比,差异均有统计学意义（P〈0．05）;与根治肾切除组相比,冷冻消融组TNF—α浓度明显升高,IL-6明显降低,差异均有统计学意义（P〈0．05）,两组IFN-γ／、IL-4浓度差异无统计学意义（P〉0．05）。结论冷冻消融冶疗肾癌可使外周血IFN-γ／、TNF-α、IFN-γ／IL-4比值升高,IL-6浓度降低,增强机体的抗肿瘤免疫功能。     

Impaired monocyte cytokine production in critically ill patients with acute renal failure

BACKGROUND: Plasma levels of pro- and anti-inflammatory cytokines are predictive of mortality in patients with acute renal failure (ARF). Anti-inflammatory strategies are postulated to be beneficial in treatment. However, there are few studies simultaneously examining monocyte cytokine production and plasma cytokine levels in patients with ARF. METHODS: Study populations consisted of 20 critically ill patients with ARF, 19 critically ill patients without ARF (CRIT ILL), 28 healthy subjects (HS), 19 patients with chronic kidney disease (CKD), and 15 patients with end-stage renal disease (ESRD). Monocyte intracellular content of interleukin-1beta (IL-1beta), interleukin-6 (IL-6), interleukin-8, and tumor necrosis factor-alpha (TNF-alpha) was determined by flow cytometry in whole blood. Plasma interleukin 6 and TNF-alpha concentrations were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: At baseline, there were no differences in intracellular monocyte cytokine levels between groups. After lipopolysaccaride stimulation, monocyte production of IL-1beta, TNF-alpha, and IL-6 in ARF patients was reduced by 41%, 84%, and 45%, respectively, compared to healthy subjects (P < 0.01 in each case), and similarly reduced compared to CKD and ESRD patients, and were similar to CRIT ILL patients. Plasma IL-6 levels were significantly higher in ARF patients than healthy subjects, CKD, and ESRD patients (all P < 0.001). CONCLUSION: Critically ill patients with acute renal failure have impaired monocyte cytokine production and elevated plasma cytokine levels in a pattern that closely resembles critically ill patients without ARF, and that is dissimilar to CKD and ESRD patients.     

IL-6/IL-6R axis plays a critical role in acute kidney injury

The response to tissue injury involves the coordination of inflammatory and repair processes. IL-6 expression correlates with the onset and severity of acute kidney injury (AKI), but its contribution to pathogenesis remains unclear. This study established a critical role for IL-6 in both the inflammatory response and the resolution of AKI. IL-6-deficient mice were resistant to HgCl2-induced AKI compared with wild-type mice. The accumulation of peritubular neutrophils was lower in IL-6-deficient mice than in wild-type mice, and neutrophil depletion before HgCl2 administration in wild-type mice significantly reduced AKI; these results demonstrate the critical role of IL-6 signaling in the injurious inflammatory process in AKI. Renal IL-6 expression and STAT3 activation in renal tubular epithelial cells significantly increased during the development of injury, suggesting active IL-6 signaling. Although a lack of renal IL-6 receptors (IL-6R) precludes the activation of classical signaling pathways, IL-6 can stimulate target cells together with a soluble form of the IL-6R (sIL-6R) in a process termed trans-signaling. During injury,serum sIL-6R levels increased three-fold, suggesting a possible role for IL-6 trans-signaling in AKI. Stimulation of IL-6 trans-signaling with an IL-6/sIL-6R fusion protein activated STAT3 in renal tubular epithelium and prevented AKI. IL-6/sIL-6R reduced lipid peroxidation after injury, suggesting that its protective effect may be largely mediated through amelioration of oxidative stress. In summary, IL-6 simultaneously promotes an injurious inflammatory response and, through a mechanism of trans-signaling, protects the kidney from further injury.     

Predictive factors of anemia within the first year post renal transplant

BACKGROUND: The aim of our study was to identify the independent factors that might predict anemia at 6 (M6) and 12 (M12) months posttransplantation. METHODS: Postrenal transplant anemia (PTA) was defined as having a hemoglobin (Hb) level below 13 g/dl for men and below 12 g/dL for women. In this study, we included all the recipients who received a renal transplant in 2001 at our department, and for whom the graft was still functioning 1 year later (n=92). RESULTS: Anemia was observed in 78%, 35.5% and 25% of patients at day (D)0 and at M6 and M12, respectively. Iron deficiency was found in 14% of patients at D0 and in 13% of patients at M12. A total of 59.8% of patients had received at least one blood transfusion in the postoperative period, whereas 41.3% of patients had received recombinant erythropoietin (rEpo) therapy within the first months posttransplantation. In multivariate analysis, the independent predictive factors of anemia at M6 were Epo level at D0, initial nephropathy (polycystic kidney disease vs. others), posttransplantation rEpo therapy, hematocrit at M3, platelets at D7, and sirolimus therapy. The independent predictive factors of anemia at M12 were Epo level at D0, platelets at D7, delayed graft function (DGF), creatinine clearance at M12, serum creatinine at M12, and Hb level at M6. CONCLUSIONS: The prevalence of PTA was 25% at M12. DGF, renal function at M12, and anemia at M6 were independent risk factors for still having anemia at M12.