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An inverse relationship between body mass index (BMI) and mortality (the obesity paradox) has been found in patients with non-dialysis-dependent chronic kidney disease (CKD). However, it is unclear whether increased muscle mass or body fat confers the survival advantage. To resolve this we investigated the impact of body makeup on a composite outcome of death or cardiovascular events in a prospective cohort of 326 patients with stage 3-5 CKD not yet on dialysis. Lean mass and body fat were determined using the Body Composition Monitor, a multifrequency bioimpedance spectroscopy device, and were expressed as the lean tissue or fat tissue index, respectively. Patients were stratified as High (above median) or Low (below median) BMI, High or Low lean tissue index, or as High or Low fat tissue index. During a median follow-up of 4.6 years, there were 40 deaths and 68 cardiovascular events. In Cox proportional hazards models, a High lean tissue index, but not High BMI or High fat tissue index, predicted a lower risk of both the composite or its component outcomes (reference: below median). When patients were further stratified into four distinct body composition groups based on both the lean and fat tissue index, only the High lean/fat tissue index group had a significantly lower risk of the composite outcome (hazard ratio 0.36, 95% confidence interval 0.14-0.87; reference: Low lean/fat tissue index group). Thus, the lean tissue index can provide better risk prediction than the BMI alone in non-dialysis-dependent patients with CKD. The High lean/fat tissue index appears to be associated with best outcomes. An optimal body composition for improving the prognosis of CKD needs to be determined.

Chronic kidney disease (CKD) is an emerging worldwide public health problem. Inflammatory cell infiltration and activation during the early stages in injured kidneys is a common pathologic feature of CKD. Here, we determined whether an important inflammatory regulator, triggering receptor expressed on myeloid cells (TREM)-1, is upregulated in renal tissues collected from mouse ureteral obstruction–induced nephritis. TREM-1 is crucial for modulating macrophage polarization, and has a pivotal role in mediating tubular injury and interstitial collagen deposition in obstructive nephritis. Lysates from nephritic kidneys triggered a TREM-1-dependent M1 polarization ex vivo , consistent with the observation that granulocyte-macrophage colony-stimulating factor (GM-CSF)-derived M1 macrophages express higher levels of TREM-1 in comparison with M-CSF-derived cells. Moreover, agonistic TREM-1 cross-link significantly strengthens the inductions of iNOS and GM-CSF in M1 cells. These observations are validated by a strong clinical correlation between infiltrating TREM-1-expressing/iNOS-positive macrophages and renal injury in human obstructive nephropathy. Thus, TREM-1 may be a potential diagnostic and therapeutic target in human kidney disease.

Diabetic nephropathy is characterized by excessive deposition of extracellular matrix protein and disruption of the glomerular filtration barrier. Matrix metalloproteinases (MMPs) affect the breakdown and turnover of extracellular matrix protein, suggesting that altered expression of MMPs may contribute to diabetic nephropathy. Here we used an MMP-9 gene knockout mouse model, with in vitro experiments and clinical samples, to determine the possible role of MMP-9 in diabetic nephropathy. After 6 months of streptozotocin-induced diabetes, mice developed markedly increased albuminuria, glomerular and kidney hypertrophy, and thickening of the glomerular basement membrane. Gelatin zymographic analysis and western blotting showed that there was enhanced MMP-9 protein production and activity in the glomeruli. However, MMP-9 knockout in diabetic mice significantly attenuated these nephropathy changes. In cultured podocytes, various cytokines related to diabetic nephropathy including TGF-β1, TNF-α, and VEGF stimulated MMP-9 secretion. Overexpression of endogenous MMP-9 induced podocyte dedifferentiation. MMP-9 also interrupted podocyte cell integrity, promoted podocyte monolayer permeability to albumin, and extracellular matrix protein synthesis. In diabetic patients, the upregulation of urinary MMP-9 concentrations occurred earlier than the onset of microalbuminuria. Thus, MMP-9 seems to play a role in the development of diabetic nephropathy.Kidney International advance online publication, 26 March 2014; doi:10.1038/ki.2014.67.

Optimal treatment algorithms for erythropoiesis-stimulating agent (ESA) and iron therapy in anemic CKD patients are lacking. Kuragano et al. evaluated hemodialysis patients over two years and report increased mortality risk and/or adverse events in those with high serum ferritin levels and high ferritin fluctuations, and an increase in adverse events in iron users. Clinical practice should avoid disproportionately high ESA or iron doses to achieve hemoglobin targets, particularly in those with significant comorbidity or ESA resistance.

Patients with chronic kidney disease have an increased prevalence of peripheral arterial disease. Endothelial progenitor cells (EPC) are pivotal in neovascularization, but their role in mediating peripheral arterial disease in chronic kidney disease is not fully known. Here we studied the impact of indoxyl sulfate, a protein-bound uremic toxin, on EPC function in response to tissue ischemia or cell hypoxia in mice that underwent subtotal nephrectomy or sham operation. At 16 weeks, unilateral hindlimb ischemia was induced in all. Four weeks later, subtotal nephrectomy mice had significantly increased plasma levels of indoxyl sulfate, reduced reperfusion, decreased EPC mobilization, and impaired neovascularization in ischemic hindlimbs compared with control mice. Treatment with AST-120, an oral adsorbent of uremic toxins, reversed these changes. Ischemia-induced protein expression including phospho-eNOS, phospho-STAT3, interleukin-10, and VEGF were significantly decreased in ischemic hindlimbs of subtotal nephrectomy mice versus control mice; all effects were reversed by AST-120. Subtotal nephrectomy mice fed a diet with indole for 12 weeks resulted in impaired neovascularization in ischemic hindlimbs; also reversed by AST-120. In cultured human EPCs, VEGF expression was increased in hypoxia through HIF-1α and interleukin-10/STAT3 signaling; effects suppressed by pretreatment with indoxyl sulfate. Moreover, indoxyl sulfate markedly attenuated hypoxia-induced EPC migration and tube formation. Thus, indoxyl sulfate may be a therapeutic target for EPC-rescue of impaired neovascularization in patients with chronic kidney disease and peripheral arterial disease.

Protective effect of vitamin C on 8-hydroxy-2′-deoxyguanosine level in peripheral blood lymphocytes of chronic hemodialysis patients.BackgroundThis study focused on the effect of vitamin C on the 8-hydroxy-2′-deoxyguanosine (8-OHdG) level of cellular DNA, as well as 8-oxoguanine-DNA glycosylase 1 (hOGG1) and human MutT homologue (hMTH1) gene expression in peripheral blood lymphocytes of chronic hemodialysis patients.MethodsSixty chronic hemodialysis patients (35 men and 25 women) were recruited to participate in a randomized, placebo-controlled study. Treatment order is block-randomized with intravenous sodium ascorbate (vitamin C, 300 mg) or placebo (0.9% saline), administered postdialysis three times a week. We evaluated 8-OHdG level, intracellular reactive oxygen species (ROS) production, and gene expression of hOGG1 and hMTH1 in peripheral blood lymphocytes byusing high-performance liquid chromatography (HPLC) electrochemical detection method, flow cytometric analysis, andreverse transcription-polymerase chain reaction (RT-PCR),respectively.ResultsA total of 51 patients completed the study (26 in placebo group and 25 in vitamin C group). Mean 8-OHdG levels significantly decreased in total subjects following 8 weeks of vitamin C supplementation (22.9 vs. 18.8/106 dG, P < 0.01). The decrease in 8-OHdG levels after vitamin C supplementation was also noted in the patients with ferritin

Effect of vitamin E-bonded membrane on the 8-hydroxy 2′-deoxyguanosine level in leukocyte DNA of hemodialysis patients.Background8-Hydroxy 2′-deoxyguanosine (8-OHdG) of leukocyte DNA has been identified as a surrogate marker of oxidative stress in chronic hemodialysis (HD) patients. In this study, we focused on the determinants of the 8-OHdG level in leukocyte DNA of HD patients. We further investigated the influence of vitamin E-modified, regenerated cellulose (CL-E) membrane on the oxidative DNA damage, intracellular reactive oxygen species (ROS) production of granulocytes, and plasma α-tocopherol concentration.Methods8-OHdG content in cellular DNA of leukocytes was measured by a high-performance liquid chromatography-electrochemical detection (HPLC-ECD) method. Intracellular production of ROS, H2O2 and O2-· were analyzed by flow cytometry in leukocytes with and without phorbol-12-myristate-13-acetate (PMA) stimulation before dialysis, as well as at 15 and 30 minutes of dialysis. Plasma α-tocopherol concentration was measured by a HPLC method, and the value of α-tocopherol was corrected by total blood lipid concentration.ResultsIn the prospective cross sectional study, the mean 8-OHdG level in leukocyte DNA was equally lower in the patients of the CL-E, polymethylmethacrylate (PMMA), and polysulfone (PS) groups as compared with the cellulosic group (ANOVA, P < 0.001). The leukocyte 8-OHdG level correlated negatively with plasma α-tocopherol and blood lipid-adjusted plasma α-tocopherol, but correlated positively with serum iron and percentage of transferrin saturation. Forward stepwise multiple regression showed that dialysis membrane type, serum iron, and blood lipid-adjusted plasma α-tocopherol were the independent determinants of the leukocyte 8-OHdG level in HD patients. Like synthetic membranes, granulocyte ROS production was less augmented during dialysis with the CL-E membrane as compared with the cellulose membrane. Exposure to cellulose membrane impaired intracellular ROS production of granulocytes in response to PMA challenge, whereas the CL-E and synthetic membranes improved the granulocyte responsiveness to PMA. In the longitudinal cross-over study, the 8-OHdG level significantly decreased, and blood lipid-adjusted plasma α-tocopherol increased after switching the cellulose membrane to CL-E or synthetic membrane for eight weeks. In contrast, the 8-OHdG level dramatically rose, and blood lipid-adjusted plasma α-tocopherol declined after shift of CL-E or synthetic membrane to the cellulose membrane.ConclusionsCL-E membrane exhibited biocompatible and bioactive characteristics. Like synthetic membranes, treatment with a CL-E dialyzer effectively reduced the 8-OHdG content in leukocyte DNA, suppressed intracellular ROS production of granulocytes, and preserved the plasma level of vitamin E. It could further improve granulocyte responsiveness to a PMA challenge. Reduced DNA damage and improved immune function of leukocytes may reduce the cancer and infection risks in chronic HD patients.

Intravenous ascorbic acid as an adjuvant therapy for recombinant erythropoietin in hemodialysis patients with hyperferritinemia.BackgroundInadequate iron mobilization and defective iron utilization may cause recombinant erythropoietin (rEPO) hyporesponsiveness in hemodialysis (HD) patients with iron overload. We have demonstrated that intravenous ascorbic acid (IVAA), but not intravenous iron medication, can effectively circumvent the functional iron-deficient erythropoiesis associated with iron overload in HD patients. However, it is uncertain whether all HD patients with hyperferritinemia will consistently respond to IVAA and which index may indicate functional iron deficiency in the special entity. Therefore, a prospective study was conducted to establish the guidelines for IVAA adjuvant therapy.MethodsSixty-five HD patients with serum ferritin levels of more than 500 μg/liter were recruited and divided into the control (N = 19) and IVAA (N = 46) groups. IVAA patients with a hematocrit (Hct) of less than 30% received 300mg of ascorbic acid three times per week for eight weeks. Controls had a Hct of more than 30% and did not receive the adjuvant therapy. Red blood cell and reticulocyte counts, iron metabolism indices, erythrocyte zinc protoporphyrin (E-ZPP), and the concentrations of plasma ascorbate and oxalate were examined before and following the therapy.ResultsThirteen patients (four controls and nine IVAA patients) withdrew by the end of the study. Eighteen patients had a dramatic response to IVAA with a significant increase in their hemoglobin and reticulocyte index and a concomitant 24% reduction in rEPO dose after eight weeks. This paralleled a significant rise in serum iron and transferrin saturation (TS) and a fall in E-ZPP and serum ferritin (baselines vs. 8weeks, serum iron 68 ± 37 vs. 124 ± 64 μg/dl, TS 27 ± 10 vs. 48 ± 19%, E-ZPP 123 ± 44 vs. 70 ± 13 μmol/mol heme, and serum ferritin 816 ± 435 vs. 587 ± 323 μg/liter, P < 0.05). Compared with responders, mean values of hemoglobin, rEPO dose, iron metabolism parameters, and E-ZPP showed no significant changes in controls (N = 15) and in non-responders (N = 19). Thirty-seven patients (18 responders and 19 non-responders) were further analyzed by receiver operating characteristic curves to seek the criteria for prediction of a response to IVAA treatment. The results showed that E-ZPP at a cut-off level of more than 105 μmol/mol heme and TS at a level of less than 25% were more specific to confirm the status of functional iron deficiency in iron-overloaded patients. The two criterion values had the highest accuracy to predict a response to treatment.ConclusionsFunctional iron-deficient erythropoiesis plays a role in rEPO-hyporesponsive anemia in HD patients with hyperferritinemia. IVAA may be an adjuvant therapy for rEPO in these patients, and E-ZPP of more than 105 μmol/mol heme and TS of less than 25% should be used to guide the IVAA treatment.

Erythropoietin hyporesponsiveness: From iron deficiency to iron overload. Iron deficiency is the most frequently encountered cause of suboptimal response to recombinant human erythropoietin (rHuEPO). Carefully assessing iron status is of paramount importance in chronic renal failure patients prior to or during rHuEPO therapy. Because there is great need for iron in the EPO-stimulated erythroid progenitors, it is essential that serum ferritin and transferrin saturation levels should be maintained over 300 μg/liter and 30%, respectively. Investigators have shown that oral iron is unlikely to keep pace with the iron demand for an optimal rHuEPO response in uremics. Therefore, patients with iron deficiency will always require intravenous iron therapy. The early and prompt iron supplementation can lead to reductions in rHuEPO dose and hence cost. After the iron deficiency has been corrected or excluded, we must remember all of the possible causes of hyporespon-siveness in every rHuEPO-treated patient. As dose requirements vary, it is not clear which dose of rHuEPO causes this hyporesponsiveness. However, if the patient with iron repletion does not respond well after the induction period, the major causes blunting the response to rHuEPO should be investigated. Most factors are reversible and remediable, except resistant anemia associated with hemoglobinopathy or bone marrow fibrosis, which requires a further increase in the rHuEPO dose. By means of early detection and correction of the possible causes, the goal of increasing therapeutic efficacy can be achieved. Iron overload may lead to an enhanced risk for infection, cardiovascular complication, and cancer. Over-treatment with iron should be avoided in dialysis patients, despite the fact that the safe upper limit of serum ferritin to avoid iron overload is not clearly defined. On the other hand, functional iron deficiency may develop even when serum ferritin levels are increased. Controversy remains as to whether intravenous iron therapy can overcome this form of hyporesponsiveness in iron-overloaded patients. Moreover, a treatment option of iron supplementation is not warranted in these patients, as the potential hazards of iron overload will be worsened. We demonstrated that the mean hematocrit significantly increased from 25.1 ± 0.9% to 31 ± 1.2% after eight weeks of intravenous ascorbate therapy (300 mg three times a week) in 12 hemodialysis patients with serum ferritin levels of more than 500 μg/liter. The enhanced erythropoiesis paralleled with a rise in transferrin saturation (27.8 ± 2.5% vs. 44.8 ± 9.5%, P < 0.05) and reductions in erythrocyte zinc protoporphyrin (130 ± 32 vs. 72 ± 19 mmol/mol heme, P < 0.05) and monthly rHuEPO dose (24.2 ± 4.5 vs. 16.8 ± 3.4 3 103units, P < 0.05) at the end of study. It is speculated that ascorbate supplementation not only facilitates the iron release from storage sites and its delivery to hematopoietic tissues, but also increases iron utilization in ery-throid cells. Our study provides a more complete understanding of the pathogenesis of iron overload-related anemia and the development of an adjuvant therapy, intravenous ascorbic acid, to the existing treatments.

Volume overload is a predictor of mortality in dialysis patients. However, the fluid status of patients with chronic kidney disease (CKD) but not yet on dialysis has not been accurately characterized. We used the Body Composition Monitor, a multifrequency bioimpedance device, to measure the level of overhydration in CKD patients, focusing on the association between overhydration and cardiovascular disease risk factors. Overhydration was the difference between the amount of extracellular water measured by the Body Composition Monitor and the amount of water predicted under healthy euvolemic conditions. Volume overload was defined as an overhydration value at and above the 90th percentile for the normal population. Of the 338 patients with stages 3–5 CKD, only 48% were euvolemic. Patients with volume overload were found to use significantly more antihypertensive medications and diuretics but had higher systolic blood pressures and an increased arterial stiffness than patients without volume overload. In a multivariate analysis, male sex, diabetes, pre-existing cardiovascular disease, systolic blood pressure, serum albumin, TNF-α, and proteinuria were independently all associated with overhydration. Thus, volume overload is strongly associated with both traditional and novel risk factors for cardiovascular disease. Bioimpedance devices may aid in clinical assessment by helping to identify a high-risk group with volume overload among stages 3–5 CKD patients.

bacteremia. Aft er removal of the permanent catheter and 6 weeks of vancomycin treatment, a polytetrafl uoroeth-ylene arteriovenous graft from the distal brachial artery just proximal to the antecubital fossa to the axillary vein over the right upper arm was placed (Figure 1a). However, during the week following surgery, she complained of an increasingly pain-ful, cold, and discolored right hand. On examination, a good bruit in the graft was noted, but the hand was cold and cyanotic with absent radial and ulnar pulses. Th e involved area extended from the right index fi nger to the thumb with dry gangrene over the index fi nger (Figure 1b). Brachial artery steal related to the graft was suspected and confi rmed by Doppler ultrasonogra-phy, which demonstrated decreased blood fl ow with a reversal during early diastole (Figure 2a) at the brachial artery distal to the arterial anastomosis, and a prominent increase in antegrade peak fl ow during systole aft er the graft was externally compressed (Figure 2b). In addition, segmental stenoses of the right radial and ulnar arteries were found. Because of worsening ischemic injury, the patient underwent surgical amputation of her right forearm below the elbow. Th e graft was preserved without liga-tion on account of generalized poor vascular condition for crea-tion of any new access. Vascular steal related to arteriovenous bridge graft in this case was probably due to peripheral vascular disease from diabetes, a large bridge graft , and inadequate col-lateral fl ow to maintain distal tissue perfusion.