Impact of anemia requiring transfusion or erythropoiesis-stimulating agents on new-onset cardiovascular events and mortality after continuous renal replacement therapy.

Anemia is common in critically ill patients undergoing continuous renal replacement therapy (CRRT). We investigated the impact of anemia requiring red blood cell (RBC) transfusion or erythropoiesis-stimulating agents (ESAs) on patient outcomes after hospital discharge in critically ill patients with acute kidney injury (AKI) requiring CRRT. In this retrospective cohort study using the Health Insurance Review and Assessment database of South Korea, 10,923 adult patients who received CRRT for 3 days or more between 2010 and 2019 and discharged alive were included. Anemia was defined as the need for RBC transfusion or ESAs. Outcomes included cardiovascular events (CVEs) and all-cause mortality after discharge. The anemia group showed a tendency to be older with more females and had more comorbidities compared to the control group. Anemia was not associated with an increased risk of CVEs (adjusted hazard ratio [aHR]: 1.05; 95% confidence interval [CI]: 0.85-1.29), but was associated with an increased risk of all-cause mortality (aHR: 1.41; 95% CI 1.30-1.53). For critically ill patients with AKI requiring CRRT, anemia, defined as requirement for RBC transfusion or ESAs, may increase the long-term risk of all-cause mortality.

Acute kidney injury in bortezomib-treated patients with multiple myeloma.

BACKGROUND: The nephrotoxicity of bortezomib, a proteasome inhibitor, has not yet been elucidated, although tumor lysis syndrome (TLS) associated with multiple myeloma (MM) has been reported to increase after introduction of the drug. This study compared the incidence and risk factors for acute kidney injury (AKI) and TLS in patients with MM after bortezomib-based chemotherapy to investigate drug-related nephrotoxicity. METHODS: From 2006 to 2017, 276 patients who underwent a first cycle of bortezomib-based chemotherapy for MM were identified in a single tertiary hospital. Laboratory TLS was defined according to the Cairo-Bishop definition. Development of AKI was assessed by AKI Network criteria within 7 days of the first chemotherapy. RESULTS: The median (interquartile range) age was 65 (56-72) years, and baseline estimated glomerular filtration rate (eGFR) was 61.3 (34.1-89.1) mL/min/1.73 m2. The incidences of AKI and laboratory TLS were 17% (n = 47) and 13% (n = 36), respectively. Ten (3.6%) subjects met both AKI and TLS criteria. Multivariate analyses showed that lower eGFR category [30-59, odds ratio (OR) 3.005 (95% confidence interval 1.163-7.976); 15-29, OR 4.225 (1.183-15.000); <15, OR 16.154 (3.831-70.920) vs ≥60, P < .001], lower serum albumin level [per 1 increase, OR 0.479 (0.256-0.871), P = .018], renal amyloidosis [OR 13.039 (4.108-44.041), P < .001] and use of acyclovir during bortezomib treatment [OR 3.689 (1.133-14.469), P = .042] were predictors of AKI. MM stages and ß-2-microglobulin were not associated with increased risk of AKI. Regarding laboratory TLS, MM stage and ß-2-microglobulin were higher in those with TLS than in others. In multivariate analyses, ß-2-microglobulin level [OR 1.204 (1.005-1.461), P = .038] and absence of high-risk chromosome abnormalities [OR 0.143 (0.022-0.588), P = .016] were associated with higher risk of TLS. CONCLUSIONS: Development of AKI was often observed in the absence of TLS in patients with MM after treatment with bortezomib. In addition, the risk factors for AKI and TLS varied widely. These findings indicate the potential nephrotoxicity of bortezomib irrespective of TLS in patients with decreased kidney function.

Recoverability of Diabetic Nephropathy of Donor Kidney After Kidney Transplantation.

Some kidney donors have diabetes, and little of their natural course of diabetic nephropathy (DN) is known. The aim of this study was to analyze the changes in pathologic lesions in the diabetic donor kidney after KT by performing protocol biopsy two weeks and one year after KT. This retrospective study included 103 patients who underwent KT, with kidneys from donors with a history of diabetes mellitus (DM). Among them, data of 34 patients who underwent biopsy two weeks and one year after KT were reviewed. Biopsy specimens were reviewed using light microscopy and electron microscopy. Glomerular basement membrane (GBM) thickness at 2 weeks and 1 year was compared. Biopsy showed that DN occurred in 29 of the 34 patients. Only trivial histological changes were observed in 22 patients (64.7%), including 5 patients who did not show DN. At one year after transplantation, there was no change in the DN histologic class in 26 patients (76.5%), and there was no statistically significant difference in the change in GBM thickness. This pattern was observed regardless of the recipient's DM or glycemic control. With this understanding, clinicians can use kidneys from DM donors with more comfort, thereby reducing the kidney discard rate.

Depression is a main determinant of health-related quality of life in patients with diabetic kidney disease.

Low health-related quality of life (HRQOL) is associated with adverse outcomes in diabetic kidney disease (DKD) patients. We examined the modifiable factors associated with low HRQOL in these patients. We enrolled 141 DKD patients. HRQOL was assessed with the Short Form 36 (SF-36) questionnaire. Low HRQOL was defined as a score > one standard deviation below the mean. Depression and anxiety were assessed with the Hospital Anxiety and Depression Scale (HADS-D and HDAS-A, respectively). The patients' median age was 65 years, and 73% were men. The prevalence rates of anxiety and depression were 8% (n = 11) and 17% (n = 24), respectively. Forty (28%) patients were identified as poor sleepers, and 40 (28%) had low physical activity levels. Anxiety, depression, and poor sleep quality were negatively correlated with SF-36 scores. Higher levels of physical activity and the estimated glomerular filtration rate (eGFR) were correlated with higher SF-36 scores, which indicated better health status. Higher depression scores (HADS-D scores) were associated with low HRQOL, independent of factors including age, sex, smoking status, comorbidities, eGFR, anemia, sleep quality, anxiety levels, and physical activity levels (odds ratio, 1.43; 95% confidence interval, 1.17-1.75). Among the clinical and psycho-physical factors, depression was a main determinant of low HRQOL in DKD patients.

Clinical value of urinary cytokines/chemokines as prognostic markers in patients with crescentic glomerulonephritis.

Crescentic glomerulonephritis (CrGN) usually requires urgent immunosuppressive treatment. However, aggressive immunosuppressive treatment is often difficult because of the patients' medical conditions or comorbidities. Prognostic markers including urinary cytokines/chemokines as noninvasive biomarkers were explored in CrGN patients. This prospective cohort study included 82 patients with biopsy-confirmed CrGN from 2002 to 2015 who were followed up for 5 years. Urine and serum cytokines/chemokines on the day of kidney biopsy were analyzed in 36 patients. The median age was 65 years and 47.6% were male. Baseline estimated glomerular filtration rate (eGFR) and interstitial fibrosis and tubular atrophy (IFTA) scores were identified as significant prognostic factors. Among patients with cytokines/chemokines measurement, increased IL-10 level was identified as an independent predictor of good prognosis, and increased levels of urinary MCP-1 and fractalkine tended to be associated with good prognosis after adjusting for baseline eGFR and IFTA score. However, semiquantitative analysis of intrarenal leukocytes did not show prognostic value predicting renal outcome or correlation with urinary cytokines/chemokines. This study supports the clinical importance of baseline eGFR and IFTA scores and suggests potential usefulness of urinary IL-10, MCP-1, and fractalkine as prognostic markers for predicting renal outcomes in patients with CrGN.

Repair phase modeling of ischemic acute kidney injury: recovery vs. transition to chronic kidney disease.

The repair mechanism after ischemic acute kidney injury (AKI) involves complex immunologic processes, which determine long-term renal outcomes. Through investigating two murine ischemia-reperfusion injury (IRI) models: bilateral IRI (BIRI) and unilateral IRI (UIRI), we aimed to determine an appropriate murine model that could simulate the recovery phase of ischemic AKI. Changes in renal function, phenotypes of kidney mononuclear cells, renal fibrosis, and intrarenal cytokine/chemokine expression were serially analyzed up to 12 weeks after IRI. Plasma creatinine and BUN concentrations increased and remained elevated in the BIRI group until 7 days but decreased to comparable levels with the sham control group at 2 weeks after surgery and thereafter, whereas plasma creatinine and BUN concentrations remained unchanged in the UIRI group. Intrarenal total leukocytes, and effector memory and activated phenotypes of CD4 and CD8 T cells markedly increased in the postischemic kidneys in both IRI groups. Expression of proinflammatory cytokines/chemokines and TGF-ß1 was enhanced in the postischemic kidneys of both IRI groups with a higher degree in the UIRI group. Importantly, intrarenal immunologic changes of the BIRI group persisted until 6 weeks despite full functional recovery. The postischemic kidneys of the UIRI group showed earlier and more pronounced proinflammatory conditions as well as more severe atrophic and fibrotic changes compared to the BIRI group. These findings support the utility of longer follow-ups of BIRI and UIRI models for investigating the adaptive repair process, which facilitates recovery of ischemic AKI and maladaptive repair process may result in AKI to CKD transition, respectively.

The presence of simple renal cysts is associated with an increased risk of albuminuria in young adults.

BACKGROUND/AIMS: The prevalence of simple renal cysts increases with age; however, they are occasionally found in adults aged < 40 years. This cross-sectional study evaluated the clinical significance of simple cysts in young adults, focusing on their associations with hematuria and albuminuria. METHODS: Adults aged < 40 years who underwent comprehensive medical examination between January 2005 and December 2013 were included. Simple renal cysts were identified by ultrasonography. RESULTS: Renal cysts were found in 276 of the 5,832 subjects (4.7%). Subjects with medullary sponge kidney (n = 1) or polycystic kidney disease (n = 5) were excluded. A single cyst and multiple cysts were found in 234 (4.0%) and 42 (0.7%) subjects, respectively. Age, high systolic blood pressure, and history of hypertension were independent risk factors for the presence of simple cysts. Simple cysts were not associated with an increased prevalence of hematuria. However, subjects with cysts showed a higher prevalence of albuminuria than those without (11.3% vs. 4.5%, p < 0.001). Multivariate analysis revealed that the existence of simple renal cysts was associated with a 2.30-fold increased prevalence of albuminuria (95% confidence interval, 1.512 to 3.519; p < 0.001) independent of other risk factors. CONCLUSION: In young adults, the presence of simple renal cysts was independently associated with an increased prevalence of albuminuria. The causal relationship needs to be elucidated in further studies.

Poly (ADP-Ribose) Polymerase Inhibitor Treatment as a Novel Therapy Attenuating Renal Ischemia-Reperfusion Injury.

Intrarenal robust inflammatory response following ischemia-reperfusion injury (IRI) is a major factor in the pathogenesis of renal injury in ischemic acute kidney injury (AKI). Although numerous studies have investigated various agents of immune modulation or suppression for ischemic AKI, few showed reproducible effects. We hypothesized that poly (ADP-ribose) polymerase (PARP) inhibitor may favorably change post-ischemic intrarenal immunologic micromilieu by reducing damage-associated molecular pattern (DAMP) signals and improve renal outcome in ischemic AKI. The effects of JPI-289 (a PARP inhibitor) on early renal injury in a murine IRI model and hypoxic HK-2 cell model were investigated. Bilateral IRI surgery was performed in three groups of 9-week-old male C57BL/6 mice (control, JPI-289 50 mg/kg, and JPI-289 100 mg/kg; n = 9-10 in each group). Saline or JPI-289 was intraperitoneally injected. Renal function deterioration was significantly attenuated in the JPI-289 treatment groups in a dose-dependent manner. Inflammatory cell infiltration and proinflammatory cytokine/chemokine expressions in the post-ischemic kidneys were also attenuated by JPI-289 treatment. JPI-289 treatment at 0.5 and 0.75 µg/ml facilitated the proliferation of hypoxic HK-2 cells. PARP inhibition with JPI-289 treatment showed favorable effects in ischemic AKI by attenuating intrarenal inflammatory cascade in a murine model and facilitating proliferation of hypoxic HK-2 cells.

Efficacy and Safety of a Balanced Salt Solution Versus a 0.9% Saline Infusion for the Prevention of Contrast-Induced Acute Kidney Injury After Contrast-Enhanced Computed Tomography.

RATIONALE & OBJECTIVE: We aimed to elucidate whether a balanced salt solution decreases the occurrence of contrast-induced acute kidney injury (CI-AKI) after contrast-enhanced computed tomography (CE-CT) as compared to 0.9% saline solution. STUDY DESIGN: A randomized clinical trial. SETTING & PARTICIPANTS: The study was performed in 14 tertiary hospitals in South Korea. Patients with estimated glomerular filtration rates (eGFRs) < 45 or <60 mL/min/1.73 m2 and additional risk factors (age ≥ 60 years or diabetes) who were undergoing scheduled CE-CT were included from December 2016 to December 2018. INTERVENTION: An open-label intervention was performed. The study group received a balanced salt solution and the control group received 0.9% saline solution as prophylactic fluids for CE-CT. OUTCOMES: The primary outcome was CI-AKI, defined by creatinine level elevation ≥ 0.5 mg/dL or 25% from baseline within 48 to 72 hours after CE-CT. Secondary outcomes included AKI defined based on the KDIGO (Kidney Disease: Improving Global Outcomes) guideline, eGFR changes, death, or requiring dialysis within 6 months after CE-CT. RESULTS: 493 patients received the study fluids. The control and study groups included 251 and 242 patients, respectively. The occurrence of CI-AKI in the study (10 [4.2%]) and control (17 [6.8%]) groups was not significantly different (P = 0.27). No significant difference was present for the secondary outcomes; AKI by the KDIGO definition (study: 19 [7.9%], control: 27 [10.8%]; P = 0.33), death/dialysis (study: 11 [4.7%], control: 9 [3.7%]; P = 0.74), and eGFR changes (study: 0.1 ± 0.2 mg/dL, control: 0.3 ± 2.8 mg/dL; P = 0.69). LIMITATIONS: This study failed to meet target enrollment. CONCLUSIONS: The risk for CI-AKI was similar after administration of a balanced salt solution and after use of 0.9% saline solution during CE-CT in higher-risk patients. FUNDING: This study was funded by CJ Healthcare (CS2015_0046). TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT02799368.

The combination of area under the curve and percentage change in estimated glomerular filtration rate predicts long-term outcome of kidney transplants.

The development of surrogate markers for long-term outcomes of kidney transplant (KT) is a focus of attention. We examined the possibility of using a combination of the area under the curve of estimated glomerular filtration rate (eGFR) for 2 years (AUCeGFR2yrs ) and percent change in eGFR between 1 and 2 years after KT (% changeeGFR1/2yr ) as a surrogate marker. We compared the predictive power of death-censored graft failure with various combinations. The combination of >2% vs ≤2% for % changeeGFR1/2yr and >1300 vs ≤1300 mL/min/month for AUCeGFR2yr had the highest Harrell C-index (0.647; 95% confidence interval [95% CI], 0.604-0.690). The death-censored graft survival rate of the group with ≤2% changeeGFR1/2yr and ≤1300 mL/min/month AUCeGFR2yr was significantly lower than those of other groups. The AUC/% change eGFR had comparable predictive power to the previously identified marker ≥30% decline in eGFR between years 1 and 3 after KT (≤-30% changeeGFR1/3yr ) (Harrell's C-index = 0.645 [95% CI 0.628-0.662] for ≤-30% changeeGFR1/3yr ). The proposed combination might be useful as a surrogate marker in KT trials because it requires a shorter surveillance period than the established marker while having comparable predictive power.

Creatinine- and cystatin C-based estimated glomerular filtration rate slopes for the prediction of kidney outcome: a comparative retrospective study.

BACKGROUND: Many studies have evaluated the usefulness of creatinine- (eGFRcr) and cystatin C-based estimated glomerular filtration rate (eGFRcys) at specific time points in predicting renal outcome. This study compared the performance of both eGFR changing slopes in identifying patients at high risk of end-stage renal disease (ESRD). METHODS: From 2012 to 2017, patients with more than three simultaneous measurements of serum creatinine and cystatin C for 1 year were identified. Rapid progression was defined as eGFR slope < - 5 mL/min/1.73 m2/year. The primary outcome was progression to ESRD. RESULTS: Overall, 1323 patients were included. The baseline eGFRcr and eGFRcys were 39 (27-48) and 38 (27-50) mL/min/1.73 m2, respectively. Over 2.9 years (range, 2.0-3.8 years) of follow-up, 134 subjects (10%) progressed to ESRD. Both the eGFRcr and eGFRcys slopes were associated with a higher risk of ESRD, independently of baseline eGFR (hazard ratio [HR] = 0.986 [0.982-0.991] and HR = 0.988 [0.983-0.993], respectively; all p <  0.001). The creatinine- and cystatin C-based rapid progressions were associated with increased risk of ESRD (HR = 2.22 [1.57-3.13], HR = 2.03 [1.44-2.86], respectively; all p <  0.001). In the subgroup analyses, the rapid progression group, defined on the basis of creatinine levels (n = 503), showed no association between the eGFRcys slope and ESRD risk (p = 0.31), whereas the eGFRcr slope contributed to further discriminating higher ESRD risk in the subjects with rapid progression based on eGFRcys slopes (n = 463; p = 0.003). CONCLUSIONS: Both eGFR slopes were associated with future ESRD risk. The eGFRcr slope was comparable with the eGFRcys slope in predicting kidney outcome.

Risk Prediction for Contrast-Induced Nephropathy in Cancer Patients Undergoing Computed Tomography under Preventive Measures.

BACKGROUND: Contrast-induced nephropathy (CIN) is a major cause of acute kidney injury in chronic kidney disease. Many cancer patients have risk factors for CIN and frequently undergo contrast-enhanced computed tomography (CECT). We aimed to develop a risk prediction model for CIN in cancer patients undergoing CECT. METHODS: Between 2009 and 2017, 2,240 cancer patients with estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m2 who underwent CECT with CIN preventive measures were included in a development cohort. Primary outcome was development of CIN, defined as 25% increase in serum creatinine within 2-6 days after contrast exposure. A prediction model was developed using logistic regression analysis. The model was evaluated for prognostic utility in an independent cohort (N = 555). RESULTS: Overall incidence of CIN was 2.5% (55/2,240). In multivariable analysis, eGFR, diabetes mellitus, and serum albumin level were identified as independent predictors of CIN. A prediction model including eGFR, serum albumin level, and diabetes mellitus was developed, and risk scores ranged from 0 to 6 points. The model demonstrated fair discriminative power (C statistic = 0.733, 95% confidence interval [CI] 0.656-0.810) and good calibration (calibration slope 0.867, 95% Cl 0.719-1.015). In the validation cohort, the model also demonstrated fair discriminative power (C statistic = 0.749, 95% CI 0.648-0.849) and good calibration (calibration slope 0.974, 95% CI 0.634-1.315). CONCLUSIONS: The proposed model has good predictive ability for risk of CIN in cancer patients with chronic kidney disease. This model can aid in risk stratification for CIN in patients undergoing CECT.

Association between diuretics and successful discontinuation of continuous renal replacement therapy in critically ill patients with acute kidney injury.

BACKGROUND: Despite aggressive application of continuous renal replacement therapy (CRRT) in critically ill patients with acute kidney injury (AKI), there is no consensus on diuretic therapy when discontinuation of CRRT is attempted. The effect of diuretics on discontinuation of CRRT in critically ill patients was evaluated. METHODS: This retrospective cohort study enrolled 1176 adult patients who survived for more than 3 days after discontinuing CRRT between 2009 and 2014. Patients were categorized depending on the re-initiation of renal replacement therapy within 3 days after discontinuing CRRT or use of diuretics. Changes in urine output (UO) and renal function after discontinuing CRRT were outcomes. Predictive factors for successful discontinuation of CRRT were also analyzed. RESULTS: The CRRT discontinuation group had a shorter duration of CRRT, more frequent use of diuretics after discontinuing CRRT, and greater UO on the day before CRRT discontinuation [day minus 1 (day - 1)]. The diuretics group had greater increases in UO and serum creatinine elevation after discontinuing CRRT. In the CRRT discontinuation group, continuous infusion of furosemide tended to increase UO more effectively. Multivariable regression analysis identified high day - 1 UO and use of diuretics as significant predictors of successful discontinuation of CRRT. Day - 1 UO of 125 mL/day was the cutoff value for predicting successful discontinuation of CRRT in oliguric patients treated with diuretics following CRRT. CONCLUSIONS: Day - 1 UO and aggressive diuretic therapy were associated with successful CRRT discontinuation. Diuretic therapy may be helpful when attempting CRRT discontinuation in critically ill patients with AKI, by inducing a favorable fluid balance, especially in oliguric patients.

Comparative Evaluation of QuantiFERON-TB Gold In-Tube and QuantiFERON-TB Gold Plus in Diagnosis of Latent Tuberculosis Infection in Immunocompromised Patients.

QuantiFERON-TB Gold Plus (QFT-Plus) is a new-generation QuantiFERON-TB Gold In-Tube (QFT-GIT) assay which has two antigen-coated tubes called TB1, which contains long peptides derived from ESAT-6 and CFP-10, and TB2, which contains the same components as TB1 and additional short peptides which potentially stimulate CD8+ T cells through the presentation of major histocompatibility complex class I. This is the first study to compare QFT-Plus and QFT-GIT for use in the diagnosis of latent tuberculosis infection (LTBI) among immunocompromised patients in the Republic of Korea. Among 317 consecutive patients who underwent screening for LTBI before solid organ or hematopoietic stem cell transplantation and tumor necrosis factor alpha inhibitor treatment, LTBI was identified in 92 (29.0%) and 88 (27.8%) patients by QFT-GIT and QFT-Plus, respectively. The rate of concordance between QFT-GIT and QFT-Plus was 93.7% (κ value, 0.860), and the indeterminate rate (3.2%) was similar between QFT-GIT and QFT-Plus. Of 20 (6.3%) samples with discordant results, 11 (55.0%) and 7 (35.0%) were positive by QFT-GIT alone and QFT-Plus alone, respectively, and 2 (15.0%) were indeterminate by each assay. The interferon gamma level in samples with discordant results ranged from 0.39 to 1.10 IU/ml, except for one sample, in which the gamma interferon level was 2.97 IU/ml only in TB2. Conclusively, there was a high degree of agreement between the results of QFT-GIT and QFT-Plus for the screening of immunocompromised patients for LTBI. The reactivity in TB2 contributed substantially to the difference between QFT-GIT and QFT-Plus, particularly in solid organ transplant candidates. The significance of the discrete responses in TB1 and TB2 of QFT-Plus needs to be explored further by means of an immunological and clinical approach in different patient groups and clinical settings.

First-year GFR slope and long-term renal outcome in IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is the most frequent primary glomerular disease and the leading cause of end-stage renal disease. We investigated clinicopathologic predictors of renal survival in patients with IgAN with a focus on glomerular filtration rate (GFR) decline slope. MATERIALS AND METHODS: We screened all patients with primary IgAN between 1995 and 2012. Renal progression was defined as doubling of serum creatinine. Using serial serum creatinine levels during the first-year, we calculated the GFR decline slopes. Further, we defined patients in the steepest GFR slope quartile as rapid decliners and those in the second steepest GFR slope quartile as slow decliners. Others were defined as nondecliners. RESULTS: Of 214 participants, baseline GFR was 81 (62, 100) mL/min/1.73 m2 , which was not different among the 3 groups. Rapid decliners and slow decliners had higher levels of urinary protein/creatinine ratio (0.88, 0.89 and 0.58 g/gCr, respectively, P < .001). Five-year renal survival was 76% in rapid decliners, 91% in slow decliners and 100% in nondecliners (P < .001, rapid or slow decliners vs nondecliners). After adjustment for clinicopathologic variables, slow decliners were associated with an 8.8-fold higher risk of progression (P = .011), and rapid decliners were associated with a 10.2-fold increased risk of progression (P = .007) compared with nondecliners. CONCLUSIONS: First-year GFR slope was associated with increased risk of renal progression, independent of proteinuria and histologic findings. Further studies are needed to investigate whether early GFR change can identify high-risk patients who benefit from immunosuppressive treatment in IgAN.

Tissue expression of tubular injury markers is associated with renal function decline in diabetic nephropathy.

AIMS: The pathogenesis of diabetic kidney disease (DKD) is complex and multifactorial; increasing evidence suggests that tubular injury and inflammatory process are involved in disease progression. We investigated the potential association of renal expression of tubular injury markers, neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and inflammatory markers, tumor necrosis factor receptor (TNFR) 1 and 2 with renal progression in pathologically proven diabetic nephropathy (DN). METHODS: We identified 122 patients with confirmed DN. After excluding patients with other coexisting renal disease or estimated glomerular filtration rate (eGFR) <30mL/min/1.73m2, 35 patients were included. Annual decline of (GFR decline slope) was calculated using linear regression analysis. Tissue tubular and glomerular expressions of NGAL, KIM-1, TNFR1, and TNFR2 were assessed using immunohistochemistry. RESULTS: Median baseline urinary protein to creatinine ratio (uPCR) was 6.76 (2.18-7.61) mg/mg Cr, median baseline eGFR was 50 (43-66) mL/min per 1.73m2, and median GFR decline slope was 15.6 (4.4-35.1) mL/min per 1.73m2 per year. Positive correlations were observed between tubular expressions of NGAL and KIM-1, and GFR decline slopes (r=0.601, p<0.001; r=0.516, p=0.001, respectively), and between tubular expressions of KIM-1 and uPCR (r=0.596, p<0.001), and between NGAL and interstitial fibrosis and tubular atrophy (IFTA) score (r=0.391, p=0.024). No correlations were found between glomerular or tubular expressions of TNFRs, and clinical parameters including GFR decline slopes. On multivariate analysis, the association between tubular expressions of KIM-1 and GFR decline slopes was dependent on uPCR. Tubular expressions of NGAL were independently associated with GFR decline slopes, with an adjusted coefficient factor of 0.290 (95% confidence interval, 0.009-0.202, p=0.038). CONCLUSIONS: These findings suggest that tubular injury plays a key role in the pathogenesis of DKD in high-risk patients. Further studies are warranted to determine whether tubular injury could be a therapeutic target in DKD.

Association of genetic variations with pharmacokinetics and lipid-lowering response to atorvastatin in healthy Korean subjects.

BACKGROUND: Statins are effective agents in the primary and secondary prevention of cardiovascular disease, but treatment response to statins varies among individuals. We analyzed multiple genetic polymorphisms and assessed pharmacokinetic and lipid-lowering responses after atorvastatin 80 mg treatment in healthy Korean individuals. METHODS: Atorvastatin 80 mg was given to 50 healthy Korean male volunteers. Blood samples were collected to measure plasma atorvastatin and lipid concentrations up to 48 hours after atorvastatin administration. Subjects were genotyped for 1,936 drug metabolism and transporter genetic polymorphisms using the Affymetrix DMET plus array. RESULTS: The pharmacokinetics and lipid-lowering effect of atorvastatin showed remarkable interindividual variation. Three polymorphisms in the SLCO1B1, SLCO1B3, and ABCC2 genes were associated with either the maximum concentration (Cmax) of atorvastatin or changes in total cholesterol or low-density lipoprotein cholesterol (LDL-C). Minor homozygotes (76.5 ng/mL) of SLCO1B1 c.-910G>A showed higher Cmax than heterozygotes (34.0 ng/mL) and major homozygotes (33.5 ng/mL, false discovery rate P=0.040). Cmax and the area under the plasma concentration curve from hour 0 to infinity (AUC∞) were higher in carriers of the SLCO1B1*17 haplotype that included c.-910G>A than in noncarriers (46.1 vs 32.8 ng/mL for Cmax; 221.5 vs 154.2 ng/mL for AUC∞). SLCO1B3 c.334G>T homozygotes (63.0 ng/mL) also showed higher Cmax than heterozygotes (34.7 ng/mL) and major homozygotes (31.4 ng/mL, FDR P=0.037). A nonsynonymous ABCC2 c.1249G>A was associated with small total cholesterol and LDL-C responses (0.23% and -0.70% for G/A vs -11.9% and -17.4% for G/G). The Cmax tended to increase according to the increase in the number of minor allele of SLCO1B1 c. -910G>A and SLCO1B3 c.334G>T. CONCLUSION: Genetic polymorphisms in transporter genes, including SLCO1B1, SLCO1B3, and ABCC2, may influence the pharmacokinetics and lipid-lowering response to atorvastatin administration.

Early, but not late, treatment with human umbilical cord blood-derived mesenchymal stem cells attenuates cisplatin nephrotoxicity through immunomodulation.

Preemptive treatment with mesenchymal stem cells (MSCs) can attenuate cisplatin-induced acute kidney injury (AKI). However, it is uncertain whether MSC treatment after the development of renal dysfunction prevents AKI progression or if MSC immunomodulatory properties contribute to MSC therapy. In this study, human umbilical cord blood (hUCB)-derived MSCs were used to compare the effects and mechanisms of early and late MSC therapy in a murine model. After cisplatin injection into C57BL/6 mice, hUCB-MSCs were administered on day 1 (early treatment) or day 3 (late treatment). With early treatment, cisplatin nephrotoxicity was attenuated as evidenced by decreased blood urea nitrogen (BUN) and reduced apoptosis and tubular injury scores on day 3 Early treatment resulted in downregulation of intrarenal monocyte chemotactic protein-1 and IL-6 expression and upregulation of IL-10 and VEGF expression. Flow cytometric analysis showed similar populations of infiltrated immune cells in both groups; however, regulatory T-cell (Treg) infiltration was 2.5-fold higher in the early treatment group. The role of Tregs was confirmed by the blunted effect of early treatment on renal injury after Treg depletion. In contrast, late treatment (at a time when BUN levels were 2-fold higher than baseline levels) showed no renoprotective effects on day 6 Neither the populations of intrarenal infiltrating immune cells (including Tregs) nor cytokine expression levels were affected by late treatment. Our results suggest that early MSC treatment attenuates renal injury by Treg induction and immunomodulation, whereas a late treatment (i.e., after the development of renal dysfunction) does not prevent AKI progression or alter the intrarenal inflammatory micromilieu.

Comparison of the long-term efficacy and safety of generic Tacrobell with original tacrolimus (Prograf) in kidney transplant recipients.

This study aimed to evaluate the long-term efficacy and safety of a generic tacrolimus (Tacrobell [TCB]) compared to the original tacrolimus (Prograf [PGF]) in kidney transplant recipients. In this retrospective observational study, we analyzed the data from 444 patients who took TCB as a first-line immunosuppressive drug and 245 patients who took PGF. The 5-year graft survival rate was 92% for patients in the PGF group and 97% for patients in the TCB group, respectively. Cox proportional hazards for a one-sided, noninferiority model showed noninferiority (upper confidence interval [CI] limit of the hazard ratio [HR]<1.2) for TCB compared to PGF (HR: 0.58; 95% CI: 0-1.14). The 5-year patient survival rate was 96% for patients in the PGF group and 97% for patients in the TCB group. Cox proportional hazards for a one-sided, noninferiority model showed noninferiority (upper confidence interval limit of the HR<2.0) for TCB compared to PGF (HR: 0.83; 95% CI: 0-1.95). The 5-year acute rejection-free graft survival rate was not significantly different between the groups (TCB 67%, PGF 68.8%; P=0.6286). The incidence of adverse events including adverse cardiovascular or cerebrovascular events, malignancies, new-onset diabetes after transplantation, and infection events did not differ significantly between the two groups. We conclude that TCB is a comparable alternative to the original tacrolimus as a first-line immunosuppressive drug. Producers of generics should support further study of their products after approval to assure physicians of their efficacy and safety.

Diagnostic performances of M-protein tests according to the clinical presentations of kidney disease.

BACKGROUND: Screening for monoclonal immunoglobulin (MIg) is critical in patients with kidney disease. METHODS: We identified 943 subjects who underwent kidney biopsy and at least one of monoclonal (M)-protein tests (serum and urine electrophoresis [EP], serum and urine immunofixation [IF], and serum free light chain [FLC] ratio). The sensitivities of several combinations of the 5 tests were examined by clinical presentations of kidney disease. RESULTS: The sensitivities of serum EP, urine EP, and the serum FLC ratio were 65%, 68%, and 71%, respectively, which were lower than those of serum IF (79%) and urine IF (87%) to detect MIg. In the nephrotic syndrome (NS) group, the panel including serum IF, urine IF, and the serum FLC ratio exhibited 100% sensitivity to identify MIg in patients with multiple myeloma (MM) or with monoclonal gammopathy of renal significance (MGRS). In subjects without NS, the panel of serum EP and serum FLC ratio detected MIg in all cases of MM, and the serum IF plus serum FLC ratio detected MIg in all cases of MGRS. CONCLUSION: This study demonstrated that the sensitivity of screening panels differed by the presenting features of kidney disease. The M-protein tests had lower sensitivity for detection of MIg in subjects with NS compared to those with other clinical presentation.