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Aims Drug prescription is difficult to manage in patients with chronic kidney disease (CKD). We assessed the prevalence and determinants of inappropriate drug prescriptions (whether contraindications or inappropriately high doses) with regard to kidney function in patients with CKD under nephrology care. We also assessed the impact of the equation used to estimate GFR on the prevalence estimates. Methods Results The CKD-REIN cohort includes 3033 outpatients with CKD (eGFR between 15 and 60 ml min(-1) 1.73 m(-2)). We examined the daily doses of pharmacological agents prescribed at study entry. Inappropriate prescription was defined as the reported prescription of either a contraindicated drug or an indicated drug at an inappropriately high dose level with regard to the patient's GFR, as estimated with the CKD-EPI equation, the de-indexed CKD-EPI equation, or the Cockcroft-Gault (CG) equation. Multivariate logistic regression was used to assess the determinants of inappropriate prescription risk. At baseline, patients' median [interquartile range] number of drugs prescribed per patient was 8 [5-10]. Half of the patients had been prescribed at least one inappropriate drug. Anti-gout, cardiovascular agents and antidiabetic agents accounted for most of the inappropriate prescriptions. The percentage of inappropriate prescriptions varied from one GFR equation to another: 52% when using the CKD-EPI equation, 47% when using the de-indexed CKD-EPI equation and 41% with the CG equation. A multiple logistic regression analysis showed significantly higher odds ratios [95% confidence interval] for inappropriate prescriptions in male patients (1.28 [1.07; 1.53]), patients with diabetes (1.34 [1.06; 1.70]), those with a high BMI (1.58 [1.25; 1.99]), and those with a low GFR (10.2 [6.02; 17.3]). The risk of having at least one inappropriate prescription increased with the number of drugs per patient (P for trend \textless 0.0001) and therefore the odds ratio was 5.88 [4.17; 8.28] for those who received at least 11 prescribed medications compared to those who received fewer than 5. Conclusion Appendix Our results emphasize the complexity of drug management for CKD patients, for whom inappropriate prescription appears to be common.

Matrix remodeling is a key feature of glomerulosclerosis secondary to diabetes or hypertension. Podocytes contribute to glomerular basement membrane (GBM) turnover by producing matrix components and matrix remodelling enzymes, including matrix metalloproteinases (MMPs). The CD40/CD154 signaling pathway modulates matrix remodeling through the synthesis of MMPs and tissue inhibitors of MMPs. Platelets are a primary blood reservoir of CD154. Here we studied, the impact of the CD154/CD40 pathway on MMP-9 expression by cultured human podocytes. The role of CD40/CD154 was evaluated upon exposure of podocytes to recombinant human CD154 (rhCD154) or activated platelet supernatants from healthy human subjects. We first showed by protein and mRNA expression that CD40 was synthesized by podocytes and detectable on kidney tissue sections. CD40 expression was acquired during podocyte differentiation and enhanced upon exposure to rhCD154. In podocytes, rhCD154 induced an increase of MMP-9 production as shown by RT-PCR, Western blot and and gelatin zymography. Activated platelet supernatants induced MMP-9 mRNA synthesis in podocytes, an effect reduced by anti-CD40 antibody. Our results underscore a potential role for platelets through the CD40/CD154 signaling pathway in the control of GBM synthesis and degradation, via its regulatory role on MMP-9 production. CD154 secretion by activated platelets may contribute to GBM alterations in proteinuric nephropathies. J. Cell. Biochem. 117: 2737-2747, 2016. © 2016 Wiley Periodicals, Inc.

The association of low blood pressure (BP) with high mortality is a characteristic for hemodialysis patients. This analysis clarifies the association of BP with mortality and stroke in Japanese hemodialysis (HD) patients and examines the association separately for patients with and without antihypertensive medication (BP meds). We analyzed 9134 patients from Japan in phases 1-4 (1999-2011) of the Dialysis Outcomes and Practice Patterns Study (DOPPS), a prospective cohort study of in-center HD patients. The association of patient systolic (SBP) and diastolic (DBP) blood pressure with all-cause and cause-specific mortality was assessed using adjusted Cox regression. A U-shaped association between BP and all-cause mortality was observed, with lowest mortality for baseline SBP 140-159 mmHg and DBP 65-74 mmHg. Both SBP and DBP were positively and monotonically associated with stroke-related death: hazard ratio (95% confidence interval) was 1.24 (1.01-1.53) per 20 mmHg higher SBP and 1.23 (1.05-1.44) per 10 mmHg higher DBP. No evidence of interaction was found between SBP and use of BP meds regarding all-cause mortality (P for interaction = 0.97); the association between SBP and stroke-related death was slightly stronger among patients not on BP meds than patients on BP meds (P for interaction = 0.09). In Japanese HD patients, both low and high BP are associated with all-cause mortality. This analysis also documents a positive and monotonic association of BP with stroke-related deaths. Although our analysis indicates that the prescription of BP meds to hypertensive patients might protect against stroke-related death, additional study is warranted.

Objective Recent studies have revealed a potential implication of CD8+ T lymphocytes in the pathogenesis of systemic lupus erythematosus (SLE) through their ability to induce tissue damage. The aim of the present study was to analyze the localization of CD8+ cells in the kidneys of patients with class III and class IV lupus nephritis and to establish correlations with histologic, biologic, and clinical features of SLE. Methods Twenty-five consecutive SLE patients with class III or class IV lupus nephritis were enrolled. Phenotype analyses of blood lymphocytes and renal immunohistochemistry studies were performed. Results CD8+ T cells were the predominant kidney-infiltrating subset of cells. The mean ± SD numbers of CD8+ T cells and CD4+ T cells were 66.2 ± 65.2/mm2 and 19.3 ± 29.4/mm2, respectively. There was a significant correlation between the percentage of blood CD3+,CD8+,DR+ cells and the total number of renal CD8+ T cells (r = 0.42, P = 0.039). Renal CD8+ T cell infiltration correlated well with the renal activity index (r = 0.63, P = 0.0007) and with high serum creatinine levels (r = 0.75, P = 0.0001). This CD8+ T cell infiltrate, which was predominantly in the periglomerular area, was correlated with cellular crescents and Bowman's capsule rupture and was associated with a poor response after conventional induction therapy. Conclusion CD8+ T lymphocytes infiltrate the periglomerular area in patients with severe (class III and class IV) lupus nephritis and are linked to a poor outcome after induction therapy. These results reveal a new potential effector pathway operant in lupus nephritis.

PURPOSE: To investigate the possibility of using combined blood oxygen level-dependent (BOLD) imaging and diffusion-weighted imaging (DWI) to detect pathological and physiological changes in renal tissue damage of the kidney induced by chronic renal hyperfiltration. MATERIALS AND METHODS: The apparent diffusion coefficient (ADC) and the T(2)* value within the inner compartments of the kidneys of 17 rats with diabetes mellitus were compared with the results obtained from a control group (N = 16). The influence of dynamic changes of the renal function on the blood-oxygen saturation was evaluated by comparing the T(2)* values before and after the active reduction of tubular transport by furosemide injection. RESULTS: All compartments of the diabetic kidney showed significantly (P < 0.05) lower T(2)*-values compared to the control group. In particular, the very low values in the outer stripe (OS) of the outer medulla (OM) (T(2)*-normal: 69.4 +/- 10.9 msec; T(2)*-diabetic: 51.4 +/- 13.9 msec) indicated either hypoxia due to hyperfiltration, or renal blood volume changes. Diffusion imaging of the same area showed significantly lower ADC values (ADC-normal: 1.45 +/- 0.26; ADC-edema: 1.19 +/- 0.25 [10(-9)m(2)/s]) that correlated with pathological findings on histopathology. The injection of furosemide significantly (P < 0.05) increased T(2)* in all compartments of both populations while the ADC remained unchanged. CONCLUSION: BOLD-contrast imaging appears to be able to depict tissue at risk from ischemia by revealing information about the balance between tubular workload and delivery of oxygen, and thus may reflect a measure of the reserve capacity. The diffusion measurements apparently reveal complementary information. Although ADC imaging is not sensitive to the current energy metabolism, it appears toreflect the pathological changes within the issue. Therefore, ADC measurements may be a sensitive indicator of the severity of ischemic lesions.

In a cross-sectional study of more than 30% of French dialysis patients (N = 7,123), we evaluated the relationships between predialysis plasma bicarbonate concentration and nutritional markers. Data including age, gender, cause of end-stage renal disease (ESRD), time on dialysis, body mass index (BMI), blood levels of midweek predialysis albumin, prealbumin, and bicarbonate were collected. Normalized protein catabolic rate (nPCR), dialysis adequacy parameters, and estimation of lean body mass (LBM) were computed from pre- and postbicarbonate-dialysis urea and creatinine levels according to the classical formulas of Garred. Average values (+/- 1 SD) were age 61 +/- 16 years, BMI 23.3 +/- 4.6 kg/m2, dialysis time 12.4 +/- 2.7 h/week, HCO3 22.8 +/- 3.5 mmol/L, albumin 38.7 +/- 5.3 g/L, prealbumin 340 +/- 90 mg/L, Kt/V 1.36 +/- 0.36, nPCR 1.13 +/- 0.32 g/kg BW/day, and LBM 0.86 +/- 0.21% of ideal LBM. A highly significant negative correlation was observed between predialysis bicarbonate levels (within a range of 16-30 mmol/L, 95% of this population) and nPCR confirmed by analysis of variance using bicarbonate classes (p < 0.0001). Bicarbonate was also negatively correlated with albumin, prealbumin, BMI, and LBM. No relationship was noted between bicarbonate and Kt/V despite a positive correlation between Kt/V and nPCR. It is likely that a persistent acidosis observed despite standard bicarbonate dialysis was caused by a high dietary protein intake which results in an increased acid load, but also overcomes the usual catabolic effects of acidosis.

In stenosis of a renal artery, angiotensin-converting enzyme inhibitor (ACEI) can induce a decrease in ipsilateral glomerular filtration. Dynamic MR imaging with gadolinium chelate enhancement was tested to detect this glomerular filtration reduction in experimental renovascular hypertension in the rat. Thirteen rats, with surgically induced left renal artery stenosis, developed hypertension and were studied before and after intravenous injection of ACEI with sequential Gd-DOTA-enhanced MR imaging. The time to onset of the tubular phase, the time of the maximal drop of signal, and the medullary signal-time curves of both kidneys were compared. Before ACEI, tubular phases were symmetric in 11 rats and slightly asymmetric in 2. Twelve rats showed ACEI-induced changes (positive test): absence of tubular phase on the left side (n = 8) or delay (n = 4) with significant differences (P.01). Tubular phases remained symmetric in one (negative test). Dynamic MR imaging can identify ACEI-induced Gd-DOTA tubular transit asymmetry, indicative of functionally significant renal artery stenoses, in rats.

Increased monocyte adhesion to the endothelial lining of blood vessels by cytokine-inducible adhesion proteins is a crucial event in inflammatory processes. Moreover, adherence is known to induce cytokine gene expression, suggesting a possible positive feedback mechanism. Therefore, we determined whether monocyte adhesion to endothelial cells (ECs) amplifies their adhesion by inducing intercellular adhesion molecule 1 (ICAM-1), and whether such positive feedback mechanism could be mediated by secretion of interleukin-1 (IL-1). Using monocyte-EC couples obtained after monocyte adhesion to ECs, and methods of quantitative polymerase chain reaction and immunofluorescence flow cytometry, we showed a biphasic increase of ICAM-1 mRNA content (2 and 16 hours) and a time-dependent increase of cell surface expression of ICAM-1, mainly on ECs, and couple adhesiveness, after monocyte adhesion to ECs. Anti-ICAM-1 monoclonal antibody inhibited 63% of the enhancement of adhesiveness induced on monocyte-EC couples by previous monocyte adhesion, suggesting that monocyte adhesion to ECs induces an increase of couple adhesiveness which is partially dependent on the ICAM-1 pathway. The early ICAM-1 mRNA induction was associated with a fast induction of IL-1 beta mRNA and a 7.7-fold increase in IL-1 beta protein in supernatant. However, 30% of this 2-hour ICAM-1 mRNA peak was abolished by recombinant soluble human IL-1 receptor, suggesting that the early ICAM-1 over-expression was partially mediated by IL-1 beta, and could be induced directly by adherence. The second ICAM-1 mRNA peak was accompanied by a marked increase in IL-1 beta mRNA and protein secretion (2.6 ng/ml). The binding to ICAM-1 did not appear to directly stimulate IL-1 beta synthesis. These results indicate that monocyte adhesion to endothelial cells appears to stimulate their own recruitment via induction of ICAM-1 thereby constituting a self-perpetuating positive feedback system.