Lacosamide dosing in patients receiving continuous renal replacement therapy.

BACKGROUND: Lacosamide is one of the anticonvulsants used in critically ill patients. This study aimed to suggest appropriate lacosamide dosing regimens in critically ill patients receiving continuous renal replacement therapy (CRRT) via Monte Carlo simulations. METHODS: Mathematical models were created using published demographic and pharmacokinetics in adult critically ill patients. CRRT modalities with different effluent rates were added into the models. Lacosamide regimens were evaluated on the probability of target attainment (PTA) using pharmacodynamic targets of trough concentrations and area under the curve within a range of 5-10 mg/L and 80.25-143 and 143-231 mg*h/L for the initial 72 h-therapy, respectively. Optimal regimens were defined from regimens that yielded the highest PTA. Each dosing regimen was tested in a group of different 10,000 virtual patients. RESULTS: Our results revealed the optimal lacosamide dosing regimen of 300-450 mg/day is recommended for adult patients receiving both CRRT modalities with 20-25 effluent rates. The dose of 600 mg/day was suggested in higher effluent rate of 35 mL/kg/h. Moreover, a patient with body weight > 100 kg was less likely to attain the targets. CONCLUSIONS: Volume of distribution, total clearance, CRRT clearance and body weight were significantly contributed to lacosamide dosing. Clinical validation of the finding is strongly indicated.

A Case of Extranodal NK/T-cell Lymphoma Infiltrating Kidneys, Presenting With Hematuria and Proteinuria With False-Positive Serum Anti-proteinase 3, and Mimicking Granulomatosis With Polyangiitis.

We report a case of misdiagnosed extranodal NK/T-cell lymphoma, nasal type, mimicking granulomatosis with polyangiitis (GPA). A 30-year-old male presented with chronic non-resolving right paranasal sinusitis for two years accompanied by multiple generalized cutaneous nodules, and subnephrotic-range proteinuria. Biopsies from skin lesions and paranasal sinuses demonstrated leukocytoclastic vasculitis and necrotizing granulomatous inflammation, respectively. Serum proteinase 3 (PR3)-antineutrophilic cytoplasmic antibody (ANCA) was positive, suggesting the diagnosis of GPA based on the 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology Classification Criteria for GPA. A kidney biopsy was not pursued due to the cause of glomerulonephritis (GN) being clinically evident, per the KDIGO 2021 GN Clinical Practice Guidelines. Immunosuppression was administered, which led to a transient improvement in clinical symptoms. However, subsequent kidney biopsy and other organ biopsies with cytogenic and molecular tests eventually confirmed extranodal NK/T-cell lymphoma infiltrating kidneys, skin, and paranasal sinuses. Physicians should always consider the possibility of hematologic malignancy in young adults presenting with multiple-organ involvement with vasculitic lesions or pauci-immune crescentic GN, albeit positive ANCA serologies. Kidney biopsy with cytogenic support should be performed to exclude threatening diseases, especially in atypical cases such as in young patients despite a context of compatible manifestations with other syndromes.

Higher blood pressure versus normotension targets to prevent acute kidney injury: a systematic review and meta-regression of randomized controlled trials.

BACKGROUND: Renal hypoperfusion is one of the most common causes of acute kidney injury (AKI), especially in shock and perioperative patients. An optimal blood pressure (BP) target to prevent AKI remains undetermined. We conducted a systematic review and meta-analysis of available randomized clinical trial (RCT) results to address this knowledge gap. METHODS: From inception to May 13, 2022, we searched Ovid Medline, EMBASE, Cochrane Library, SCOPUS, clinicaltrials.gov, and WHO ICTRP for RCTs comparing higher BP target versus normotension in hemodynamically unstable patients (shock, post-cardiac arrest, or surgery patients). The outcomes of interest were post-intervention AKI rate and renal replacement therapy (RRT) rate. Two investigators independently screened the citations and reviewed the full texts for eligible studies according to a predefined form. RESULTS: Twelve trials were included, enrolling a total of 5759 participants, with shock, non-cardiac, and cardiac surgery patients accounting for 3282 (57.0%), 1687 (29.3%) and 790 (13.7%) patients, respectively. Compared to lower mean arterial blood pressure (MAP) targets that served as normotension, targeting higher MAP had no significant effect on AKI rates in shock (RR [95% CI] = 1.10 [0.93, 1.29]), in cardiac-surgery (RR [95% CI] = 0.87 [0.73, 1.03]) and non-cardiac surgery patients (RR [95% CI] = 1.25 [0.98, 1.60]) using random-effects meta-analyses. In shock patients with premorbid hypertension, however, targeting MAP above 70 mmHg resulted in significantly lower RRT risks, RR [95%CI] = 1.20 [1.03, 1.41], p < 0.05. CONCLUSIONS: Targeting a higher MAP in shock or perioperative patients may not be superior to normotension, except in shock patients with premorbid hypertension. Further studies are needed to assess the effects of a high MAP target to preventing AKI in hypertensive patients across common settings of hemodynamic instability. Trial registration This systematic review has been registered on PROSPERO ( CRD42021286203 ) on November 19, 2021, prior to data extraction and analysis.

Discovery and validation of circulating miRNAs for the clinical prognosis of severe dengue.

BACKGROUND: Early prognostic markers of severe dengue may improve case management and reduce dengue-related mortalities. This study aimed to identify circulating microRNAs (miRNAs) as biomarkers for predicting severe dengue. METHODOLOGY: Serum samples from dengue-infected patients were collected on the first day of admission. Patients were followed up for 14 days after admission to determine the final diagnosis. Participants were divided into non-severe and severe dengue, as defined by WHO 2009 criteria. Circulating microtranscriptome analysis was performed using NanoString miRNA Expression Assay. The expression level of candidate miRNAs were then validated by quantitative reverse transcription-PCR method. PRINCIPAL FINDINGS: The discovery cohort (N = 19) lead to the identification of 37 differentially expressed miRNAs between the two groups. Six up-regulated candidate miRNAs were selected and further validated in the larger cohort (N = 135). MiR574-5p and miR1246 displayed the highest diagnostic performance in discriminating between severe from non-severe dengue (ROC-AUC = 0.83). Additionally, miR574-5p and miR1246 had high sensitivity and high negative predictive value for detecting severe dengue. Multivariate analysis suggested that serum miR574-5p was an independent predictor of severe dengue (odds ratio 3.30, 95% CI 1.81-6.04; p<0.001). CONCLUSION: Our study indicated that circulating miRNAs, especially miR-574-5p and miR-1246, might be a promising diagnostic and prognostic biomarker for severe dengue upon hospital admission, especially when using these biomarkers on days 1 to 2 before the onset of severe dengue complications.

Citrate pharmacokinetics in critically ill liver failure patients receiving CRRT.

Citrate has been proposed as anticoagulation of choice in continuous renal replacement therapy (CRRT). However, little is known about the pharmacokinetics (PK) and metabolism of citrate in liver failure patients who require CRRT with regional citrate anticoagulation (RCA). This prospective clinical PK study was conducted at King Chulalongkorn Memorial Hospital between July 2019 to April 2021, evaluating seven acute liver failure (ALF) and seven acute-on-chronic liver failure (ACLF) patients who received CRRT support utilizing RCA as an anticoagulant at a citrate dose of 3 mmol/L. For evaluation of the citrate PK, we delivered citrate for 120 min and then stopped for a further 120 min. Total body clearance of citrate was 152.5 ± 50.9 and 195.6 ± 174.3 mL/min in ALF and ACLF, respectively. The ionized calcium, ionized magnesium, and pH slightly decreased after starting citrate infusion and gradually increased to baseline after stopping citrate infusion. Two of the ACLF patients displayed citrate toxicity during citrate infusion, while, no ALF patient had citrate toxicity. In summary, citrate clearance was significantly decreased in critically ill ALF and ACLF patients receiving CRRT. Citrate use as an anticoagulation in these patients is of concern for the risk of citrate toxicity.

Rapid and sensitive point-of-care detection of Leptospira by RPA-CRISPR/Cas12a targeting lipL32.

BACKGROUND: One of the key barriers preventing rapid diagnosis of leptospirosis is the lack of available sensitive point-of-care testing. This study aimed to develop and validate a clustered regularly-interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 12a (CRISPR/Cas12a) platform combined with isothermal amplification to detect leptospires from extracted patient DNA samples. METHODOLOGY/PRINCIPAL FINDINGS: A Recombinase Polymerase Amplification (RPA)-CRISPR/Cas12a-fluorescence assay was designed to detect the lipL32 gene of pathogenic Leptospira spp. The assays demonstrated a limit of detection (LOD) of 100 cells/mL, with no cross-reactivity against several other acute febrile illnesses. The clinical performance of the assay was validated with DNA extracted from 110 clinical specimens and then compared to results from qPCR detection of Leptospira spp. The RPA-CRISPR/Cas12a assay showed 85.2% sensitivity, 100% specificity, and 92.7% accuracy. The sensitivity increased on days 4-6 after the fever onset and decreased after day 7. The specificity was consistent for several days after the onset of fever. The overall performance of the RPA-CRISPR/Cas12a platform was better than the commercial rapid diagnostic test (RDT). We also developed a lateral flow detection assay (LFDA) combined with RPA-CRISPR/Cas12a to make the test more accessible and easier to interpret. The combined LFDA showed a similar LOD of 100 cells/mL and could correctly distinguish between known positive and negative clinical samples in a pilot study. CONCLUSIONS/SIGNIFICANCE: The RPA-CRISPR/Cas12 targeting the lipL32 gene demonstrated acceptable sensitivity and excellent specificity for detection of leptospires. This assay might be an appropriate test for acute leptospirosis screening in limited-resource settings.

Dengue pre-vaccination screening test evaluation for the use of dengue vaccine in an endemic area.

BACKGROUND: The dengue vaccine (Dengvaxia) is only recommended for individuals with prior dengue infection (PDI). This study aimed to perform a serosurvey to inform decision-making for vaccine introduction and identify appropriate target populations. We also evaluated the performance of the serological tests using plaque reduction neutralization test (PRNT) as a reference test in identifying PDI to determine suitability for pre-vaccination screening. METHODS: We enrolled 115 healthy individuals between 10 and 22 years of age living in the Ratchaburi province of Thailand. The serum samples were tested by PRNT to measure the prevalence and concentration of serotype-specific neutralizing antibodies. The performance of the IgG rapid diagnostic test (RDT, SD Bioline, Korea) and IgG enzyme-linked immunosorbent assay (ELISA, EUROIMMUN, Germany) in identifying PDI were evaluated by using PRNT as a reference method. RESULTS: Ninety-four (81.7%) individuals neutralized one or more dengue serotypes at a titer threshold greater than or equal to 10. Multitypic profiles were observed in 70.4% of the samples which increased to 91.9% in subjects aged 19-22. Among monotypic samples, the highest proportion was reactive against DENV-1 followed by DENV-2, DENV-3, and DENV-4. The highest anti-dengue antibody titers were recorded against DENV-1 and increased with age to a geometric mean NT50 titer (GMT) of 188.6 in the 19-22 age group. While both RDT and ELISA exhibited 100% specificity, RDT demonstrated low sensitivity (35%) with ELISA displaying much greater sensitivity (87%). CONCLUSIONS: Almost 80% of adolescents and youth in Ratchaburi province had already been exposed to one or more of the dengue virus serotypes. The dengue IgG RDT displayed low sensitivity and is likely not be suitable for dengue pre-vaccination screening. These results support the use of IgG ELISA test for dengue vaccination in endemic areas.

Comprehensive versus standard care in post-severe acute kidney injury survivors, a randomized controlled trial.

BACKGROUND: Currently, there is a lack of evidence to guide optimal care for acute kidney injury (AKI) survivors. Therefore, post-discharge care by a multidisciplinary care team (MDCT) may improve these outcomes. This study aimed to demonstrate the outcomes of implementing comprehensive care by a MDCT in severe AKI survivors. METHODS: This study was a randomized controlled trial conducted between August 2018 to January 2021. Patients who survived severe AKI stage 2-3 were enrolled and randomized to be followed up with either comprehensive or standard care for 12 months. The comprehensive post-AKI care involved an MDCT (nephrologists, nurses, nutritionists, and pharmacists). The primary outcome was the feasibility outcomes; comprising of the rates of loss to follow up, 3-d dietary record, drug reconciliation, and drug alert rates at 12 months. Secondary outcomes included major adverse kidney events, estimated glomerular filtration rate (eGFR), and the amount of albuminuria at 12 months. RESULTS: Ninety-eight AKI stage 3 survivors were enrolled and randomized into comprehensive care and standard care groups (49 patients in each group). Compared to the standard care group, the comprehensive care group had significantly better feasibility outcomes; 3-d dietary record, drug reconciliation, and drug alerts (p < 0.001). The mean eGFR at 12 months were comparable between the two groups (66.74 vs. 61.12 mL/min/1.73 m2, p = 0.54). The urine albumin: creatinine ratio (UACR) was significantly lower in the comprehensive care group (36.83 vs. 177.70 mg/g, p = 0.036), while the blood pressure control was also better in the comprehensive care group (87.9% vs. 57.5%, p = 0.006). There were no differences in the other renal outcomes between the two groups. CONCLUSIONS: Comprehensive care by an MDCT is feasible and could be implemented for severe AKI survivors. MDCT involvement also yields better reduction of the UACR and better blood pressure control. Trial registration Clinicaltrial.gov: NCT04012008 (First registered July 9, 2019).

The role of leptospiremia and specific immune response in severe leptospirosis.

Leptospirosis can cause a high mortality rate, especially in severe cases. This multicenter cross-sectional study aimed to examine both host and pathogen factors that might contribute to the disease severity. A total of 217 leptospirosis patients were recruited and divided into two groups of non-severe and severe. Severe leptospirosis was defined by a modified sequential organ failure assessment (mSOFA) score of more than two or needed for mechanical ventilation support or had pulmonary hemorrhage or death. We found that leptospiremia, plasma neutrophil gelatinase-associated lipocalin (pNGAL), and interleukin 6 (IL-6) at the first day of enrollment (day 1) and microscopic agglutination test (MAT) titer at 7 days after enrollment (days 7) were significantly higher in the severe group than in the non-severe group. After adjustment for age, gender, and the days of fever, there were statistically significant associations of baseline leptospiremia level (OR 1.70, 95% CI 1.23-2.34, p = 0.001), pNGAL (OR 9.46, 95% CI 4.20-21.33, p < 0.001), and IL-6 (OR 2.82, 95% CI 1.96-4.07, p < 0.001) with the severity. In conclusion, a high leptospiremia, pNGAL, and IL-6 level at baseline were associated with severe leptospirosis.

Levetiracetam dosing in patients receiving continuous renal replacement therapy.

OBJECTIVE: The study was aimed to define appropriate levetiracetam dosing regimens from available published pharmacokinetics (PK) studies in critically ill patients with and without cirrhosis receiving continuous renal replacement therapy (CRRT) via Monte Carlo simulation (MCS). METHODS: Mathematical pharmacokinetic models were developed using published demographic and PK data in adult critically ill patients with known variability and correlations between PK parameters. CRRT modalities (continuous venovenous hemofiltration and continuous venovenous hemodialysis) with different effluent rates were modeled. Levetiracetam regimens from available clinical resources were evaluated on the probability of target attainment (PTA) using pharmacodynamics (PD) target of the trough concentrations and area under the time-concentration curve within a range of 6-20 mg/L and 222-666 mg × hour/L for the initial 72 hours of therapy, respectively. Optimal regimens were defined from regimens that yielded the highest PTA. Each regimen was tested in a group of different 10,000 virtual patients. RESULTS: Our results showed the optimal levetiracetam dosing regimen of 750-1000 mg every 12 hours is recommended for adult patients receiving both CRRT modalities with two different effluent rates of 25 and 35 mL/kg/h. Child-Pugh class C cirrhotic patients undergoing CRRT required lower dosing regimens of 500-750 mg every 12 ours due to smaller non-renal clearance. Of interest, some of literature-based dosing regimens were not able to attain the PK and PD targets. SIGNIFICANCE: Volume of distribution, non-renal clearance, CRRT clearance, and body weight were significantly correlated with the PTA targets. Dosing adaptation in this vulnerable population should be concerned. Clinical validation of our finding is absolutely needed.

Development and validation of point-of-care testing of albuminuria for early screening of chronic kidney disease.

INTRODUCTION: Chronic kidney disease (CKD) is a significant global health issue. As the prevalence of renal replacement therapy (RRT) in Thailand is increasing, early detection and management of CKD is the most important step to prevent CKD progression and the need for RRT. Current diagnostic tests for CKD are non-specific and expensive. We aimed to develop and validate antibody-based-albumin point-of-care testing (POCT) to detect patients with impaired kidney function at early stage. METHODS: The prototype strip test was developed under the concept of competitive lateral flow immunochromatography assay, or strip test. Monoclonal antibodies (MAbs) to human serum albumin (HSA) were harvested from the hybridomas of spleen cells from immunized mice and mouse myeloma cells. Presence of MAbs was detected by enzyme-linked immunosorbent assay (ELISA). Spot urine was obtained from patients with kidney disease, type I, or type II Diabetes Mellitus upon their visit at King Chulalongkorn Memorial Hospital during 2018-2019. All samples were analyzed for urine albumin with our POCT (CU microalbumin) and the other two commercial POCTs (Microalbu PHAN and MICRAL). The results were validated against standard method for urine microalbumin measurement. A urine microalbumin concentration of less than 20 ug/ml was defined as normal. The sensitivity, specificity, and predictive values were calculated in comparison with the standard laboratory method. RESULT: A total of 100 adult patients were included. CU microalbumin had a sensitivity of 86%, a specificity of 94%, and a positive predictive value of 96%. Our POCT showed good correlation with the laboratory results. CONCLUSION: CU microalbumin correlated well with the standard method for quantitative measurement of urine albumin. Therefore, it has the potential for early screening of CKD, especially in primary health care facilities in resource limited settings.

Meropenem dosing recommendations for critically ill patients receiving continuous renal replacement therapy.

PURPOSES: To gather available meropenem pharmacokinetics and define drug dosing regimens for Asian critically ill patients receiving CRRT. METHODS: All necessary pharmacokinetic and pharmacodynamic data from Asian population were gathered to develop mathematic models with first order elimination. Meropenem concentration-time profiles were calculated to evaluate efficacy based on the probability of target attainment (PTA) of 40%fT>4MIC. A group of 5000 virtual patients was created and tested using Monte Carlo simulations for each dose in the models. The optimal dosing regimens were defined as the doses achieved at least 90% of the PTA. RESULTS: The recommended meropenem dosing regimen for Asian critically ill patients receiving CRRT with standard (20-25 mL/kg/h) and high (35 mL/kg/h) effluent rates was 750 mg q 8 h to manage Gram negative infections with expected MIC < 2 mg/L in virtual Asian patients. Some meropenem dosages from available clinical resources could not achieve the aforementioned target. The volume of distribution, body weights and nonrenal clearance significantly contributed to drug dosing adaptation especially in the specific population. CONCLUSIONS: A meropenem regimen of 750 mg q 8 h was recommended for Asian critically ill patients receiving 2 different CRRT modalities with standard and high effluent rates. Clinical validation of these results is needed.

The role of serum cystatin C in estimation of renal function in survivors of critical illness.

PURPOSE: Estimating renal function by serum creatinine after critical illness is a challenging problem. However, the role of cystatin C for estimation of the renal function in survivors of critical illness is unknown. We aimed to compare the performance of serum cystatin C- and serum creatinine-based eGFR against a reference GFR using 99mTc-diethylenetriaminepentaacetic acid (99mTc-DTPA) in survivors of critical illness. MATERIAL AND METHODS: Survivors of critical illness with stable hemodynamics and renal functions were recruited. Their serum creatinine and cystatin C levels were measured. eGFR were calculated by using various equations: 1)CKD-EPI SCysC; 2) Thai eGFR SCysC; 3)CKD-EPI SCr; 4)Thai eGFR SCr; 5)MDRD Caucasian SCr; 6)CKD-EPI SCr-SCysC. The 99mTc-DTPA plasma clearance was used as a standard eGFR. RESULTS: Forty-two patients were included. The bias (median percentage difference) between standard GFR and SCysC-based eGFR were 41.97% (95%CI 33.1% to 48.5%) for CKD-EPI SCysC and 31.72% (95%CI 21.1% to 34.9%) for Thai eGFR SCysC. While, the bias between standard GFR and SCr-based eGFR were -11.37 (95%CI -20.9 to 1.6) for CKD-EPI SCr, -18.30 (95%CI -26.3 to -10.6) for Thai eGFR SCr, and -27.17 (-43.7 to -19.1) for MDRD Caucasian SCr. CONCLUSION: In survivors of critical illness, we demonstrated limitations of estimating GFR by both currently available SCysC and SCr-based equations. Therefore, further studies are still needed to develop better eGFR equations.

Epidemiology and short-term outcomes of acute kidney injury among patients in the intensive care unit in Laos: a nationwide multicenter, prospective, and observational study.

BACKGROUND: Acute kidney injury (AKI) has become a global health issue. Little is known about the disease burden in Laos. We aimed to evaluate the burden and outcomes of AKI as well as assess the availability of AKI treatment in Laos. METHODS: We performed a multicentric prospective observational study in adult patients who had been admitted to 5 intensive care units (ICU) in Laos. The data was serially collected on the first 28 days of ICU admission. Patients were diagnosed by the KDIGO 2012 criteria for AKI. We used AKI occurrence as the primary outcome and explored risk factors on the development and outcomes of AKI. RESULTS: We enrolled 1480 patients from 5 ICU centers across Laos from January to December 2016. After excluding patients with end-stage renal disease and those with incomplete data, AKI occurred in 508 of the 1460 enrolled patients (34.8%). Overall, the rates of maximum AKI staging were 4% for stage 1, 10.3% for stage 2, and 20.5% for stage 3. Risk factors for AKI were older age, obesity, cardiovascular diseases, respiratory diseases, renal diseases, oncologic diseases, and chronic kidney diseases. Only 1.8% of all participants received RRT. The mortality rate was 28.4% in non-AKI patients compared to 44.5% in AKI patients, which increased according to the stage of AKI (stage 1, 4.9%; stage 2, 28.3%; stage 3 66.8%; P < 0.001). There were 13.6% who were discharged against medical advice. CONCLUSIONS: AKI is a huge burden in Laos with under-recognition and poor outcomes.

Urine Neutrophil Gelatinase-associated Lipocalin (NGAL) for Prediction of Persistent AKI and Major Adverse Kidney Events.

We aimed to determine whether urinary neutrophil gelatinase-associated lipocalin (uNGAL) can accurately predict persistent AKI, major adverse kidney events at 30 days (MAKE30) and 365 days (MAKE365) in hospitalized AKI patients. This is a retrospective study of adult patients who were admitted at King Chulalongkorn Memorial Hospital. We performed multivariable logistic regression for persistent AKI, MAKE30, and MAKE365. We developed equations for predicting MAKE30 and MAKE365 and divided the dataset into derivation and validation cohorts. uNGAL performance and predictive models were assessed using the area under the receiver operating characteristic curve (AROC). Among 1,322 patients with AKI, 76.9%, 45.1%, and 61.7% had persistent AKI, MAKE30, and MAKE365. The AROC were 0.75 (95% confidence interval[CI] 0.70-0.80), 0.66 (95%CI 0.61-0.71), and 0.64 (95%CI 0.59-0.70) for prediction of persistent AKI, MAKE30, and MAKE365 by uNGAL. The AROC in the validation dataset combining uNGAL with clinical covariates were 0.74 (95%CI 0.69-0.79) and 0.72 (95%CI 0.67-0.77) for MAKE30 and MAKE365. We demonstrated an association between uNGAL and persistent AKI, MAKE30, and MAKE365. Prediction models combining uNGAL can modestly predict MAKE30 and MAKE365. Therefore, uNGAL is a useful tool for improving AKI risk stratification.

Clinical and subclinical acute kidney injury in multidrug-resistant septic patients treated with colistimethate sodium: Incidence and clinical outcomes.

AIM: Colistimethate sodium (CMS) has been postulated as the principal cause of high incidence of clinical acute kidney injury (AKI) in multidrug-resistance (MDR) septic patients with normal baseline serum creatinine (sCr) who were treated with CMS. This prospective observational study was conducted to examine the incidence and clinical outcomes of clinical and subclinical AKI in MDR septic patients receiving CMS. METHODS: Forty-two MDR septic patients with normal sCr who required CMS were included. Clinical AKI was diagnosed by increased sCr levels according to the KDIGO2012 criteria while subclinical AKI was identified by elevated levels of urinary neutrophil gelatinase-associated lipocalin (uNGAL > 150 ng/mL) or urinary liver-type fatty-acid-binding protein (uL-FABP > 10.5 ng/mL). RESULTS: Clinical AKI was noted in 47.6% of patients on day 5 and 38.1% on day 7 after initiating CMS. By using uL-FABP, subclinical AKI was observed in 45.2% and 54.8% on day 5 and 7, respectively. At baseline prior to CMS treatment, subclinical AKI was already present in 90%. The baseline uL-FABP was superior to the baseline uNGAL in early prediction of clinical AKI on day 5. The subclinical AKI patients had comparable worse outcomes as clinical AKI patients. CONCLUSION: The incidence of subclinical AKI in MDR septic patients before CMS treatment was extremely high. The baseline uL-FABP provided the best predictive capacity of clinical AKI. The causes of clinical AKI might include the persistence of sepsis process, subclinical AKI and CMS nephrotoxicity. Proper management of subclinical AKI patients before CMS initiation should be concerned to prevent further renal damage and improve patient and renal outcomes.

Plasma miR-370-3P as a Biomarker of Sepsis-Associated Encephalopathy, the Transcriptomic Profiling Analysis of Microrna-Arrays From Mouse Brains.

The diagnosis of sepsis-associated encephalopathy (SAE), an alteration of conscious from sepsis, is difficult due to the similarity to altered states of conscious that occur from other causes. Transcriptomic analyses between mouse brains at 24 h after cecal ligation and puncture (CLP) (SAE brain as evaluated by SHIRPA score) and at 120 h post-CLP (survivor) were performed to discover the SAE biomarker. Then, candidate microRNAs were validated in mouse and patient samples.As such, increased miR-370-3p in SAE mouse-brains (compared with recovery phase) was demonstrated by transcriptomic miR-profiling and was highly expressed in brain (but not other organs) of 24 h post-CLP mice. Plasma miR-370-3p also increased in CLP but was non-detectable in bilateral-nephrectomy (BiNx, a representative model of acute uremic encephalopathy) despite blood brain barrier permeability defect (determined by plasma s100ß and Evan blue dye assay) in both conditions. In parallel, high plasma miR-370-3p was demonstrated in patients with SAE (but not sepsis alone or uremia) suggesting the specificity toward SAE. The association among TNF-α, miR-370-3p and brain apoptosis was demonstrated by high serum TNF-α and increased brain apoptosis in SAE mice, TNF-α (but not other cytokines) activated miR-370-3p expression in PC-12 neuron cell, and increased cell apoptosis in miR-370-3p transfected PC-12 after incubation with TNF-α.In conclusion, miR-370-3p increased in brain and plasma of SAE mice but not uremic encephalopathy. Perhaps, TNF-α enhances cell susceptibility toward brain apoptosis in SAE, in part, through miR-370-3p induction in neuron. Our pilot results in patients with SAE supported the possibility that plasma miR-370-3p is an interesting SAE biomarker candidate. Further studies are warranted.

Factors associated with erythropoiesis-stimulating agent hyporesponsiveness anemia in chronic kidney disease patients.

Anemia is one of the most common problems in chronic kidney disease (CKD). Despite comprehensive investigations in several cases, definite causes of anemia frequently remain unknown. Our study aimed to analyze the factors that possibly affect anemia in CKD patients who were referred for hematology consultation. A total of 87 patients were retrospectively included in the cohort. Forty-four cases were excluded, including 30 cases with unavailable intact parathyroid hormone (iPTH) data, 11 cases with bone marrow diseases (8 Pure red cell aplasia, 3 Myelodysplastic syndrome) and 3 cases with thalassemia. In total, 43 patients were analyzed. Patients with high iPTH had a significantly lower Hemoglobin (Hb) level and required a higher dose of erythropoiesis stimulating agents (ESAs) compared with the normal iPTH group (Hb 8.29 vs 9.24 mg/dL, P=0.032 and ESAs dose of 16,352.94 vs. 12,444.44 U/week, P=0.024). Univariate, followed by stepwise multivariate analysis was performed and determined that serum phosphate (PO4) was significantly associated with lower Hb level (P=0.01 and P=0.013, respectively). In addition, Hb level was inversely correlated with iPTH and serum phosphate (PO4) level (r=-0.54, P<0.001 and r=-0.47, P=0.005; respectively). Mineral disequilibrium is an important factor associated with anemia in ESA hyporesponsive CKD. Also, hyperphosphatemia and secondary hyperparathyroidism are significantly correlated with low Hb. As a result, we strongly suggest correction of mineral disequilibrium factors prior to performing bone marrow study.

The efficacy of blind versus real-time ultrasound-guided percutaneous renal biopsy in developing country.

INTRODUCTION: Renal biopsy is a useful diagnostic procedure. In developing countries, two techniques of renal biopsy, blind percutaneous renal biopsy and real-time ultrasound-guided percutaneous renal biopsy, have been performed. The majority of studies compared these using different types and sizes of biopsy needle. The aim of this study was to compare both techniques in resource constraint country. METHOD: We reviewed renal biopsy database, between 1 January 2014 to 30 June 2017. The primary outcome was the total number of glomeruli. The other outcomes were tissue adequacy and bleeding complications. We also analyzed multivariable logistic regression to find factors associated with tissue adequacy and bleeding complications. RESULT: Of the 204 renal biopsies, 100 were blind percutaneous renal biopsy and 104 real-time ultrasound-guided percutaneous renal biopsy. The number of native renal biopsies was 169 (82.8%). Baseline characteristics of two groups were comparable. The mean number of total glomeruli from real-time ultrasound-guided percutaneous renal biopsy was significantly more than blind percutaneous renal biopsy (20.8 ± 12.1 vs 16.0 ± 13.0, p = 0.001). The real-time ultrasound-guided percutaneous renal biopsy obtained more adequate tissues than blind percutaneous renal biopsy (45.2% vs 16%, p < 0.001) and was the only factor associated with adequate tissue. Moreover, 16 renal biopsies from blind percutaneous renal biopsy obtained inadequate tissue. The overall bleeding complications were not statistically different. We found being female, lower eGFR and lower hematocrit were associated with bleeding complications. CONCLUSION: In comparison with blind percutaneous renal biopsy, real-time ultrasound-guided percutaneous renal biopsy obtained more adequate tissue and number of glomeruli. While the complications of both were comparable. We encourage to practice and perform real-time ultrasound-guided percutaneous renal biopsy in resource constraint countries.

Furosemide Stress Test as a Predicting Biomarker for Delayed Graft Function in Kidney Transplantation.

BACKGROUND: Delayed graft function (DGF) could worsen early and long-term outcomes of kidney transplantation (KT). DGF is caused by several pre-transplantation and perioperative factors in both donors and recipients. At present, there are no biomarkers or tests during the immediate post-KT period that can accurately predict the development of DGF. MATERIALS AND METHODS: This prospective study was conducted in deceased donor KT (DDKT) at King Chulalongkorn Memorial Hospital, Thailand. All recipients underwent furosemide stress test (FST) by receiving a single dose of intravenous furosemide, 1.5 mg/kg at 3 h after allograft reperfusion. We determined the correlations between DGF (requiring dialysis within the first week after transplantation) and the values of urine volume recorded hourly after FST until 6 h, the parameters of postoperative dynamic tests, including resistive index (RI) of renal arteries and effective renal plasma flow (ERPF), and urine neutrophil gelatinase-associated lipocalin (NGAL). RESULTS: Of the 59 total DDKT recipients enrolled, 24 developed DGF. The FST is a more accurate biomarker than urine NGAL, RI of renal arteries, and ERPF in the prediction of DGF. The 4-h urine volume less than 350 mL (FST non-responsive) was the best cut-off value in predicting DGF with 87.5% sensitivity, 82.9% specificity, and 82.5% accuracy. Multiple logistic regression analyses showed an odds ratio of 0.993 (0.986-0.999, p = 0.035) for the 4-h urine volume to predict DGF. CONCLUSIONS: The FST is a simple and accurate biomarker for predicting DGF in early post-KT period. Close monitoring and well prepared dialysis are suggested in patients with urine volume < 350 mL after 4 h of FST. The FST non-responsive patients could be the target for further DGF preventive intervention. ClinicalTrials.gov identifier: NCT03071536.