Daisuke Katagiri

Evaluation of new acute kidney injury biomarkers in a mixed intensive care unit.

Objective:Biomarkers for detection of acute kidney injury and prediction of mortality will be useful to improve the outcomes of critically ill patients. Although several promising acute kidney injury biomarkers have been reported, evaluation in heterogeneous disease-oriented populations is necessary to confirm their reliability before their translation to clinical use. This study was undertaken to evaluate the reliability of new acute kidney injury biomarkers including urinary L-type fatty acid-binding protein with heterogeneous intensive care unit populations. Design:Prospective observational cohort study. Setting:Single-center study, 15-bed medical–surgical mixed intensive care unit at a university hospital. Patients:Three hundred thirty-nine adult critically ill patients who had been admitted to the intensive care unit were studied prospectively. Interventions:None. Measurements and Main Results:Five urinary biomarkers (L-type fatty acid-binding protein, neutrophil gelatinase-associated lipocalin, interleukin-18, N-acetyl-&bgr;-D-glucosaminidase, and albumin) were measured at intensive care unit admission. By the RIFLE (Risk, Injury, Failure, Loss, End-stage kidney disease) criteria, 131 patients (39%) were diagnosed as acute kidney injury. Urinary L-type fatty acid-binding protein detected acute kidney injury better than the other biomarkers did (the area under the receiver operating characteristic curves for L-type fatty acid-binding protein 0.75, neutrophil gelatinase-associated lipocalin 0.70, interleukin-18 0.69, N-acetyl-&bgr;-D-glucosaminidase 0.62, albumin 0.69). Urinary L-type fatty acid-binding protein predicted later-onset acute kidney injury after intensive care unit admission with the highest area under the receiver operating characteristic curve value of 0.70. Furthermore, L-type fatty acid-binding protein, neutrophil gelatinase-associated lipocalin, and interleukin-18 were able to predict 14-day mortality with higher area under the receiver operating characteristic curves than acute kidney injury detection (area under the receiver operating characteristic curve for L-type fatty acid-binding protein 0.90, neutrophil gelatinase-associated lipocalin 0.83, interleukin-18 0.83). The combination of L-type fatty acid-binding protein and neutrophil gelatinase-associated lipocalin improved mortality prediction (area under the receiver operating characteristic curve 0.93). Conclusion:This prospective observational study with a cohort of heterogeneous patients treated in a mixed intensive care unit revealed that new acute kidney injury biomarkers have a significantly and moderately predictive use for acute kidney injury diagnosis and that urinary L-type fatty acid-binding protein and neutrophil gelatinase-associated lipocalin can serve as new biomarkers of mortality prediction in critical care.

Mild elevation of urinary biomarkers in prerenal acute kidney injury

Prerenal acute kidney injury (AKI) is thought to be a reversible loss of renal function without structural damage. Although prerenal and intrinsic AKI frequently coexist in clinical situations, serum creatinine and urine output provide no information to support their differentiation. Recently developed biomarkers reflect tubular epithelial injury; therefore, we evaluated urinary biomarker levels in an adult mixed intensive care unit (ICU) cohort of patients who had been clinically evaluated as having prerenal AKI. Urinary L-type fatty acid-binding protein (L-FABP), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), N-acetyl-β-D-glucosaminidase (NAG), and albumin in patients with prerenal AKI showed modest but significantly higher concentrations than in patients with non-AKI. We also conducted a proof-of-concept experiment to measure urinary biomarker excretion in prerenal AKI caused by volume depletion. Compared with cisplatinum and ischemia-reperfusion models in mice, volume depletion in mice caused a modest secretion of L-FABP and NGAL into urine with more sensitive response of L-FABP than that of NGAL. Although no histological evidence of structural damage was identified by light microscopy, partial kidney hypoxia was found by pimonidazole incorporation in the volume depletion model. Thus, our study suggests that new AKI biomarkers can detect mild renal tubular damage in prerenal acute kidney injury.

Protection of Glucagon-Like Peptide-1 in Cisplatin-Induced Renal Injury Elucidates Gut-Kidney Connection

Accumulating evidence of the beyond-glucose lowering effects of a gut-released hormone, glucagon-like peptide-1 (GLP-1), has been reported in the context of remote organ connections of the cardiovascular system. Specifically, GLP-1 appears to prevent apoptosis, and inhibition of dipeptidyl peptidase-4 (DPP-4), which cleaves GLP-1, is renoprotective in rodent ischemia-reperfusion injury models. Whether this renoprotection involves enhanced GLP-1 signaling is unclear, however, because DPP-4 cleaves other molecules as well. Thus, we investigated whether modulation of GLP-1 signaling attenuates cisplatin (CP)-induced AKI. Mice injected with 15 mg/kg CP had increased BUN and serum creatinine and CP caused remarkable pathologic renal injury, including tubular necrosis. Apoptosis was also detected in the tubular epithelial cells of CP-treated mice using immunoassays for single-stranded DNA and activated caspase-3. Treatment with a DPP-4 inhibitor, alogliptin (AG), significantly reduced CP-induced renal injury and reduced the renal mRNA expression ratios of Bax/Bcl-2 and Bim/Bcl-2. AG treatment increased the blood levels of GLP-1, but reversed the CP-induced increase in the levels of other DPP-4 substrates such as stromal cell-derived factor-1 and neuropeptide Y. Furthermore, the GLP-1 receptor agonist exendin-4 reduced CP-induced renal injury and apoptosis, and suppression of renal GLP-1 receptor expression in vivo by small interfering RNA reversed the renoprotective effects of AG. These data suggest that enhancing GLP-1 signaling ameliorates CP-induced AKI via antiapoptotic effects and that this gut-kidney axis could be a new therapeutic target in AKI.

The value of QuantiFERON®TB-Gold in the diagnosis of tuberculosis among dialysis patients

BACKGROUND It is difficult to diagnose tuberculosis (TB) in dialysis patients because of the high rate of extrapulmonary TB in these patients compared with the general population. Recently, a new diagnostic test called QuantiFERON (QFT) has been developed and shown promise as a diagnostic tool for active TB diseases and latent TB infection. METHODS We examined 162 dialysis patients admitted to a single institute, including 8 patients with active TB, and evaluated the utility of this test in dialysis patients. RESULTS Among 162 dialysis patients, positive QFT results occurred in 28 (17.3%), negative QFT results occurred in 95 (58.6%) and indeterminate QFT results occurred in 39 (24.1%). All eight active TB patients had positive QFT results, and none of the 95 patients with negative results had active TB. Among 23 patients with a history of active TB, 10 (43.5%) had positive results. Although the indeterminate rate was relatively high, no patient with an indeterminate result had active TB. Factors such as shorter duration of dialysis, lower lymphocyte count and higher white blood cell count were associated with indeterminate results. Among 105 cases after excluding the patients with previous TB or indeterminate results, the sensitivity of the QFT is 100% (8 of 8) and the specificity is 89.7% (87 of 97 cases). CONCLUSIONS Our data suggest that the QFT test is a useful supplementary tool for the diagnosis of active TB even in dialysis patients. Negative and indeterminate results on this test may be used to exclude the presence of active TB.

New biomarker panel of plasma neutrophil gelatinase–associated lipocalin and endotoxin activity assay for detecting sepsis in acute kidney injury

PURPOSE Septic acute kidney injury (AKI) shows an unacceptably high mortality rate. Detection of sepsis is important for the clinical management of AKI patients. This study was undertaken to evaluate 2 biomarkers of neutrophil gelatinase-associated lipocalin (NGAL) and endotoxin activity (EA) assay and their combination for detecting sepsis in AKI. MATERIALS AND METHODS Adult intensive care unit patients consisting of 40 non-AKI, 65 AKI without sepsis, 10 non-AKI with sepsis, and 24 septic AKI were examined in a cross-sectional manner. Plasma NGAL and EA values in whole blood were measured at recruitment. We evaluated whether combining 2 different biomarkers would improve the performance of each biomarker using receiver operating characteristic analysis. RESULTS Plasma NGAL was significantly higher in septic AKI patients than in the other AKI patients and non-AKI patients, whereas EA values were higher in septic patients than nonseptic patients irrespective of AKI complication. Combination of plasma NGAL and EA value increased the area under the curve of the receiver operating characteristic curve and showed better performance compared with a clinical model consisting of clinically available variables. CONCLUSION Combinations of plasma NGAL and EA, which are operating via different pathological pathways, significantly improved their detection performance in complicated conditions of septic AKI.

A 5-hydroxytryptamine receptor antagonist sarpogrelate reduces renal tubulointerstitial fibrosis by suppressing PAI-1

A selective 5-hydroxytryptamine (5-HT) 2A receptor antagonist sarpogrelate (SG) blocks serotonin-induced platelet aggregation. It has been used clinically for the treatment of peripheral arterial disease. SG might be able to improve chronic ischemia, which contributes to renal fibrosis progression by maintaining renal microcirculation. This study investigated whether SG suppresses renal fibrosis. C57BL/6 mice fed a 0.2% adenine-containing diet for 6 wk developed severe tubulointerstitial fibrosis with kidney dysfunction. Subsequent SG treatment (30 mg·kg(-1)·day(-1)) for 4 wk improved these changes significantly by increasing peritubular blood flow in the fibrotic area, as evaluated by intravital microscopy and decreasing fibrin deposition. Urinary L-type fatty acid-binding protein, up-regulated by renal hypoxia, was also reduced by SG. Additionally, results showed that mRNA expression of plasminogen activator inhibitor-1 (PAI-1), which is known to promote fibrosis by mediating and enhancing transforming growth factor (TGF)-β1 signaling, was suppressed by SG treatment in the kidney. In vitro experiments using cultured murine proximal tubular epithelial (mProx) cells revealed that incubation with TGF-β1 and 5-HT increased PAI-1 mRNA expression; SG significantly reduced it. In conclusion, SG reduces renal fibrosis not only by the antithrombotic effect of maintaining peritubular blood flow but also by suppressing PAI-1 expression in renal tubular cells.

Antiepoetin antibody-related pure red cell aplasia: successful remission with cessation of recombinant erythropoietin alone

An elderly patient with pure red cell aplasia (PRCA) with antierythropoietin (anti-EPO) antibodies is described. PRCA due to alloimmunization is a rare and severe complication of recombinant human erythropoietin (rHu-EPO) therapy. Most reported patients with PRCA were cured primarily by immunosuppressive drug therapy. The patient in this case, however, did not want to receive any immunosuppressive drugs. Therefore, rHu-EPO injection was simply discontinued, the severe anemia gradually improved, and the hemoglobin approached normal range. This case is very rare and significant in that there have been few such elderly patients with rHu-EPO-induced PRCA in whom PRCA remission was achieved, with decreasing antibody titers, after cessation of rHu-EPO alone. Further cases are needed to assess how PRCA should be treated in patients with anti-EPO antibodies.

Multiple Myeloma and Kidney Disease

Multiple myeloma (MM) has a high incidence rate in the elderly. Responsiveness to treatments differs considerably among patients because of high heterogeneity of MM. Chronic kidney disease (CKD) is a common clinical feature in MM patients, and treatment-related mortality and morbidity are higher in MM patients with CKD than in patients with normal renal function. Recent advances in diagnostic tests, chemotherapy agents, and dialysis techniques are providing clinicians with novel approaches for the management of MM patients with CKD. Once reversible factors, such as hypercalcemia, have been corrected, the most common cause of severe acute kidney injury (AKI) in MM patients is tubulointerstitial nephropathy, which results from very high circulating concentrations of monoclonal immunoglobulin free light chains (FLC). In the setting of AKI, an early reduction of serum FLC concentration is related to kidney function recovery. The combination of extended high cutoff hemodialysis and chemotherapy results in sustained reductions in serum FLC concentration in the majority of patients and a high rate of independence from dialysis.

Factors associated with recovery of renal function in patients with multiple myeloma who were treated with hemodialysis.

Background: The presence of renal failure in patients with multiple myeloma (MM) has been considered an ominous prognostic factor associated with a significantly decreased life expectancy. The prognostic factors have seldom been analyzed to predict discontinuation of hemodialysis (HD) therapy in MM patients with renal failure after HD initiation. It is clinically very important to predict whether HD can be discontinued after introducing HD in such patients. Methods: All medical and HD records were reviewed in MM patients who underwent HD in the National Center for Global Health and Medicine Hospital between January 1995 and May 2009. Thirty-two patients with MM had undergone HD. The clinical features and the factors that might be associated with recovery of renal function leading to discontinuation of HD in MM patients with severe renal failure were examined. Results: The factors associated with recovery of renal function and discontinuation of HD were: low International Staging System (ISS) score (p = 0.0034); high response to chemotherapy (p = 0.036); low serum Ca (p = 0.006); low Cr (p = 0.019), and low serum β2-microglobulin (sβ2M) (p = 0.002). On multivariate analysis, low serum Ca and sβ2M were significantly associated with HD discontinuation. Moreover, discontinuing HD was the significant factor associated with improved overall survival in MM patients who required HD at least once. Conclusion: sβ2M and Ca were the laboratory parameters that were significant, independent prognostic factors for predicting the probability of recovery from severe renal failure and discontinuation of HD in MM patients who needed HD at least once.

Deep vein puncture under ultrasonographic guidance-an alternative approach for vascular access of apheresis therapies.

To the Editor: Granulocyte monocyte apheresis (GMA) is one of the modalities in apheresis that is reported to be clinically effective for inflammatory bowel diseases (IBD) [1]. Those who suffer from IBD often experience dehydration and for whom the vascular access is difficult to be placed due to collapse of superficial veins. When we consider the blood flow of upper limbs, blood flow from the brachial artery must enter into either superficial or deep veins. Even if superficial veins do not accept sufficient blood flow, it can be considered that blood is drained through deep veins. Ultrasonography (US) guided central vein puncture has been reportedly related to improving success rate and to reduce complications [2,3]. The procedure was also used for deep veins in emergency department for intravenous access [4]. We have developed and reported the procedure of US-guided vascular access puncture on hemodialysis patients [5]. We also have applied this method to GMA patients who have difficult vascular accesses. In order to elucidate usefulness of US-guided deep vein puncture, we retrospectively evaluated the medical charts of the patients who required such access puncture methods. From June 2013 to January 2015, we investigated the patients: (1) who received GMA therapy, (2) for whom we could not draw sufficient blood flow from superficial veins, and (3) whose deep veins were punctured under US guidance. The effectiveness and adverse events were assessed from the medical chart of such patients. Actual procedures were reported previously [5]. We describe them here in brief. We used a portable US device, Nanomaxx (Covidien Japan, Tokyo, Japan) with linear probe (6–13 MHz) for the current procedure. We investigate the direction of the deep vein under longitudinal view. Next, we place the probe perpendicular to the vein. At this time, the positions of vital structures such as brachial arteries and median veins nerves are identified in relation to the target deep vein, so that we should not damage them during the procedure (Fig. 1). Thereafter, we puncture the vein under US guidance. Once the tip of the needle is observed on the screen, we gradually thrust the needle little by little. After we place the needle in proper place, we remove the inner needle and complete the puncture. In total, we applied this method to four patients with ulcerative colitis. Their ages range from 26 to 63 years old. The reasons why we selected the deep veins as vascular access are as follows: (1) damaged superficial veins due to repeated cannulation in one patient, (2) small sized superficial veins probably by nature in two, and (3) dehydration due to discontinuation of fluid therapy after amelioration of IBD in one. In total 33 sessions of GMA were performed on them with Adacolumn (JIMRO, Takasaki, Japan). Blood flow rate was kept as 30 mL/min and session length was set as 60 min. Needle size was uniformly set as 17 Gauge. All of the sessions were completed without interruption, although most of the sessions (23 sessions) required tourniquet. No adverse events such as injury of the arteries or nerves, or bleeding complications were experienced. We demonstrated that deep vein puncture under US guidance can be a useful strategy for GMA procedure on those whose superficial veins accept only inadequate blood flow for the therapy. Deep veins as the