Effects of poly (ADP-ribose) polymerase inhibitor treatment on the repair process of ischemic acute kidney injury.

Excessive activation of poly (ADP-ribose) polymerase (PARP) contributes to ischemic acute kidney injury (AKI). PARP inhibition has been shown to be beneficial in renal ischemia-reperfusion injury (IRI) in the early phase, but its role in the repair process remains unclear. The effects of JPI-289, a novel PARP inhibitor, during the healing phase after renal IRI were investigated. IRI was performed on 9-week-old male C57BL/6 mice. Saline or JPI-289 100 mg/kg was intraperitoneally administered once at 24 h or additionally at 48 h after IRI. Hypoxic HK-2 cells were treated with JPI-289. Renal function and fibrosis extent were comparable between groups. JPI-289 treatment caused more prominent tubular atrophy and proinflammatory intrarenal leukocyte phenotypes and cytokines/chemokines changes at 12 weeks after unilateral IRI. JPI-289 treatment enhanced gene expressions associated with collagen formation, toll-like receptors, and the immune system in proximal tubules and endothelial cells after IRI. JPI-289 treatment at 3 or 6 h after hypoxia facilitated proliferation of hypoxic HK-2 cells, whereas further treatment after 24 h suppressed proliferation. Delayed inhibition of PARP after renal IRI did not facilitate the repair process during the early healing phase but rather may aggravate renal tubular atrophy during the late healing phase in ischemic AKI.

Prognostic significance of albuminuria in elderly of various ages with diabetes.

It remains uncertain whether albuminuria can identify elderly patients with diabetes at a high risk of incident end-stage kidney disease (ESKD) or mortality. 3065 patients (aged ≥ 65 years) with type 2 diabetes were included. We examined the association between albuminuria stages (normoalbuminuria, A1; microalbuminuria, A2; and macroalbuminuria, A3) and the risk of incident ESKD and all-cause mortality for each age group (65-69, 70-74, and ≥ 75 years). A2 and A3 were observed in 25.5% and 9.4% of the subjects, respectively. For A1, A2, and A3, the probabilities of ESKD at 8 years were 1.0%, 6.3%, and 29.7% (P < 0.001 for all), and the all-cause mortality was 13.1%, 27.4%, and 31.7% (P < 0.001 for A1 vs A2, P < 0.001 for A1 vs A3), respectively. Albuminuria stages were independently associated with an increased risk of ESKD [fully adjusted hazard ratios (HR): 3.650 (1.987-6.702) for A2, 10.404 (5.706-18.972) for A3 vs. A1]. The HRs of all-cause mortality were 1.742 (1.411-2.153) for A2 and 1.810 (1.344-2.441) for A3. The associations between albuminuria stages and the risk of ESKD and all-cause mortality were consistent across all age groups. Even microalbuminuria is also a risk factor for incident ESKD and mortality in elderly patients with diabetes.

The impact of preoperative kidney replacement therapy on kidney outcome and survival in patients with left ventricular assist device.

Left ventricular assist device (LVAD) has been highlighted as a new treatment option in the end-stage heart failure (HF). Kidney outcome after LVAD in severe cardiorenal syndrome (CRS) patients requiring kidney replacement therapy (KRT) is unclear. We investigated the impact of preoperative KRT on kidney function and survival in LVAD patients with severe CRS. A total of 50 patients followed up for at least 1 year after LVAD implantation was analyzed. The primary outcomes were estimated glomerular filtration rate and survival rate. Patients were divided into two groups depending on in-hospital KRT before LVAD implantation: the control group (n = 33) and the KRT group (n = 17). Postoperative KRT was performed for 76.5% of patients in the KRT group, and all of them discontinued KRT before discharge. There were no statistically significant differences in the degree of eGFR decline in survivors according to preoperative KRT. Although there were no statistically significant differences in the degree of eGFR decline in survivors regardless of preoperative KRT, old age (ß -0.94, p < 0.01), preexisting chronic kidney disease (ß -21.89, p < 0.01), and high serum creatinine (ß -13.95, p < 0.01) were identified as independent predictors of post-LVAD eGFR decline. Mortality rate was higher, and more patients progressed to end-stage kidney disease in KRT group than control group. However, LVAD still can be considered as the treatment option in end-stage HF patients with severe CRS requiring KRT, especially in those with young age and previous normal kidney function.

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.

Impact of protocolized fluid management on electrolyte stability in patients undergoing continuous renal replacement therapy.

Objective: Continuous renal replacement therapy (CRRT) is the standard treatment for critically ill patients with acute kidney injury (AKI). Electrolyte disturbance such as hypokalemia or hypophosphatemia occurs paradoxically in patients undergoing CRRT due to high clearance. We developed a fluid management protocol for dialysate and replacement fluid that depends on serum electrolytes and focuses on potassium and phosphate levels to prevent electrolyte disturbance during CRRT. The impact of our new fluid protocol on electrolyte stability was evaluated. Methods: Adult patients who received CRRT between 2013 and 2017 were included. Patients treated 2 years before (2013-2014; pre-protocol group) and 2 years following development of the fluid protocol (2016-2017; protocol group) were compared. The primary outcomes were individual coefficient of variation (CV) and abnormal event rates of serum phosphate and potassium. Secondary outcomes were frequency of electrolyte replacement and incidence of cardiac arrhythmias. Individual CV and abnormal event rates for each electrolyte were analyzed using the Wilcoxon rank-sum test and Chi-square test with Yates' continuity correction. Results: A total of 1,448 patients was included. Both serum phosphate and potassium were higher in the protocol group. The CVs of serum phosphate (pre-protocol vs. protocol, 0.275 [0.207-0.358] vs. 0.229 [0.169-0.304], p < 0.01) and potassium (0.104 [0.081-0.135] vs. 0.085 [0.064-0.110], p < 0.01) were significantly lower in the protocol group. The abnormal event rates of serum phosphate (rate [95% CI], 0.410 [0.400-0.415] vs. 0.280 [0.273-0.286], p < 0.01) and potassium (0.205 [0.199-0.211] vs. 0.083 [0.079-0.087], p < 0.01) were also significantly lower in the protocol group. Conclusion: The protocolized management of fluid in CRRT effectively prevented hypophosphatemia and hypokalemia by inducing excellent stability of serum phosphate and potassium levels.

Clinical relevance of postoperative proteinuria for prediction of early renal outcomes after kidney transplantation.

BACKGROUND: Proteinuria is associated with poor allograft and patient survival in kidney transplant recipients. However, the clinical relevance of spot urine protein-to-creatinine ratio (PCR) or albumin-to-creatinine ratio (ACR) as predictors of renal outcomes during the early postoperative period following kidney transplantation (KT) has not been determined. METHODS: This single-center retrospective cohort study included 353 kidney transplant recipients who underwent KT between 2014 and 2017 and were followed up for more than 3 years. Among them, 186 and 167 recipients underwent living donor KT and deceased donor KT, respectively. The PCR and ACR were measured during the immediate postoperative period (within 7 days postoperatively), before discharge (2-3 weeks postoperatively), and 3-6 months postoperatively. RESULTS: The median age of the patients was 51 years (interquartile range, 43-59 years), and 62.9% were male. An immediate postoperative PCR of ≥1 mg/mg was associated with old age, diabetes mellitus, high systolic blood pressure, delayed graft function, and donor factors (deceased donor KT, old age, and high serum creatinine concentrations). The PCR and ACR 3 to 6 months posttransplant were inversely associated with the estimated glomerular filtration rate at 1 year posttransplant. Deceased donor KT recipients with immediate postoperative PCR of ≥3 mg/mg showed a greater incidence of delayed graft function and lower estimated glomerular filtration rate before discharge than those with immediate postoperative PCR of <3 mg/mg. CONCLUSION: Early postoperative proteinuria is a useful biomarker to predict early renal outcomes after KT.

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.

Early postoperative urinary MCP-1 as a potential biomarker predicting acute rejection in living donor kidney transplantation: a prospective cohort study.

We investigated the clinical relevance of urinary cytokines/chemokines reflecting intrarenal immunologic micromilieu as prognostic markers and the optimal measurement timing after living donor kidney transplantation (LDKT). This prospective cohort study included 77 LDKT patients who were followed for ≥ 5 years. Patients were divided into control (n = 42) or acute rejection (AR, n = 35) group. Early AR was defined as AR occurring within 3 months. Serum and urine cytokines/chemokines were measured serially as follows: intraoperative, 8/24/72 h, 1 week, 3 months, and 1 year after LDKT. Intrarenal total leukocytes, T cells, and B cells were analyzed with immunohistochemistry followed by tissueFAXS. Urinary MCP-1 and fractalkine were also analyzed in a validation cohort. Urinary MCP-1 after one week was higher in the AR group. Urinary MCP-1, fractalkine, TNF-α, RANTES, and IL-6 after one week were significantly higher in the early AR group. Intrarenal total leukocytes and T cells were elevated in the AR group compared with the control group. Urinary fractalkine, MCP-1, and IL-10 showed positive correlation with intrarenal leukocyte infiltration. Post-KT 1 week urinary MCP-1 showed predictive value in the validation cohort. One-week post-KT urinary MCP-1 may be used as a noninvasive diagnostic marker for predicting AR after LDKT.

Predialysis predictors for identifying patients requiring dialysis at a higher glomerular filtration rate.

BACKGROUND: Current evidence suggests that the initiation of maintenance hemodialysis should not be based on a specific glomerular filtration rate (GFR) but on symptoms or signs attributable to kidney disease. However, it is difficult to predict the time point at which overt uremic syndrome develops in individuals. The estimated GFR is poorly correlated with occurrence of uremic symptoms, and some patients require dialysis at a higher eGFR than others. In this case, patients are more likely to be improperly prepared for dialysis. We investigated the predialysis characteristics of patients who require dialysis at a higher eGFR. METHODS: A total of 453 incident dialysis patients being monitored by a nephrologist from January 2013 to December 2018 were included. The predialysis characteristics when eGFR decreased to 20 mL/min/1.73 m2 were obtained. RESULTS: The mean age was 61 years, and 65.7% were men. Overall, the median eGFR at the first dialysis was 5.8 (interquartile range 4.6-7.3) mL/min/1.73 m2 and initiation of dialysis at the first quintile (≥7.8 mL/min/1.73 m2) was defined as 'early initiation of dialysis' Among the predialysis characteristics, heart failure (adjusted odds ratio 3.68; 95% confidence interval, 1.59-8.03), serum albumin <4.0 mg/dL (2.22; 1.30-3.77), blood urea nitrogen (BUN)/creatinine (Cr) ratio >15 mg/mg (1.92, 1.16-3.18), and hyperuricemia (1.84; 1.05-3.23) were independent predictors of early initiation. Diabetes mellitus and the causes of kidney disease were not independent predictors of early initiation. The early initiation group was less likely to initiate dialysis with a permanent vascular access than the late initiation group. CONCLUSIONS: For patients with heart failure, low serum albumin level, high BUN/Cr ratio, or hyperuricemia, clinicians can provide predialysis counseling in advance and consider early creation of vascular access.

Dietary Modification Alters the Intrarenal Immunologic Micromilieu and Susceptibility to Ischemic Acute Kidney Injury.

The versatility of the intrarenal immunologic micromilieu through dietary modification and the subsequent effects on susceptibility to ischemic acute kidney injury (AKI) are unclear. We investigated the effects of high-salt (HS) or high-fat (HF) diet on intrarenal immunologic micromilieu and development of ischemic AKI using murine ischemic AKI and human kidney-2 (HK-2) cell hypoxia models. Four different diet regimens [control, HF, HS, and high-fat diet with high-salt (HF+HS)] were provided individually to groups of 9-week-old male C57BL/6 mice for 1 or 6 weeks. After a bilateral ischemia-reperfusion injury (BIRI) operation, mice were sacrificed on day 2 and renal injury was assessed with intrarenal leukocyte infiltration. Human kidney-2 cells were treated with NaCl or lipids. The HF diet increased body weight and total cholesterol, whereas the HF+HS did not. Although the HF or HS diet did not change total leukocyte infiltration at 6 weeks, the HF diet and HF+HS diet increased intrarenal CD8 T cells. Plasma cells increased in the HF and HS diet groups. The expression of proinflammatory cytokines including TNF-α, IFN-γ, MCP-1, and RANTES was increased by the HF or HS diet, and intrarenal VEGF decreased in the HS and HF+HS diet groups at 6 weeks. Deterioration of renal function following BIRI tended to be aggravated by the HF or HS diet. High NaCl concentration suppressed proliferation and enhanced expression of TLR-2 in hypoxic HK-2 cells. The HF or HS diet can enhance susceptibility to ischemic AKI by inducing proinflammatory changes to the intrarenal immunologic micromilieu.

A Scoring Model with Simple Clinical Parameters to Predict Successful Discontinuation of Continuous Renal Replacement Therapy.

BACKGROUND: Continuous renal replacement therapy (CRRT) is the standard treatment for severe acute kidney injury in critically ill patients. However, a practical consensus for discontinuing CRRT is lacking. We aimed to develop a prediction model with simple clinical parameters for successful discontinuation of CRRT. METHODS: Adult patients who received CRRT at Samsung Medical Center from 2007 to 2017 were included. Patients with preexisting ESRD and patients who progressed to ESRD within 1 year or died within 7 days after CRRT were excluded. Successful discontinuation of CRRT was defined as no requirement for renal replacement therapy for 7 days after discontinuing CRRT. Patients were assigned to either a success group or failure group according to whether discontinuation of CRRT was successful or not. RESULTS: A total of 1,158 patients were included in the final analyses. The success group showed greater urine output on the day before CRRT discontinuation (D-1) and the discontinuation day (D0). Multivariable analysis identified that urine output ≥300 mL on D-1, and mean arterial pressure 50∼78 mm Hg, serum potassium <4.1 mmol/L, and BUN <35 mg/dL (12.5 mmol/L) on D0 were predictive factors for successful discontinuation of CRRT. A scoring system using the 4 variables above (area under the receiver operating curve: 0.731) was developed. CONCLUSIONS: Scoring system composed of urine output ≥300 mL/day on D-1, and adequate blood pressure, serum potassium <4.1 mmol/L, and BUN <35 mg/dL (12.5 mmol/L) on D0 was developed to predict successful discontinuation of CRRT.

Comparison of the Efficacy and Safety of Tacrolimus and Low-Dose Corticosteroid with High-Dose Corticosteroid for Minimal Change Nephrotic Syndrome in Adults.

BACKGROUND: Tacrolimus is used as a steroid-sparing immunosuppressant in adults with minimal change nephrotic syndrome. However, combined treatment with tacrolimus and low-dose steroid has not been compared with high-dose steroid for induction of clinical remission in a large-scale randomized study. METHODS: In this 24-week open-label noninferiority study, we randomized 144 adults with minimal change nephrotic syndrome to receive 0.05 mg/kg twice-daily tacrolimus plus once-daily 0.5 mg/kg prednisolone, or once-daily 1 mg/kg prednisolone alone, for up to 8 weeks or until achieving complete remission. Two weeks after complete remission, we tapered the steroid to a maintenance dose of 5-7.5 mg/d in both groups until 24 weeks after study drug initiation. The primary end point was complete remission within 8 weeks (urine protein: creatinine ratio <0.2 g/g). Secondary end points included time until remission and relapse rates (proteinuria and urine protein: creatinine ratio >3.0 g/g) after complete remission to within 24 weeks of study drug initiation. RESULTS: Complete remission within 8 weeks occurred in 53 of 67 patients (79.1%) receiving tacrolimus and low-dose steroid and 53 of 69 patients (76.8%) receiving high-dose steroid; this difference demonstrated noninferiority, with an upper confidence limit below the predefined threshold (20%) in both intent-to-treat (11.6%) and per-protocol (17.0%) analyses. Groups did not significantly differ in time until remission. Significantly fewer patients relapsed on maintenance tacrolimus (3-8 ng/ml) plus tapered steroid versus tapered steroid alone (5.7% versus 22.6%, respectively; P=0.01). There were no clinically relevant safety differences. CONCLUSIONS: Combined tacrolimus and low-dose steroid was noninferior to high-dose steroid for complete remission induction in adults with minimal change nephrotic syndrome. Relapse rates were significantly lower with maintenance tacrolimus and steroid compared with steroid alone. No clinically-relevant differences in safety findings were observed.

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.

Urinary angiotensinogen as a surrogate marker predicting the antiproteinuric effects of angiotensin receptor blockers in patients with overt proteinuria: a multicenter prospective study.

BACKGROUND: Although urinary angiotensinogen (AGT) and renin reflect intrarenal renin-angiotensin system activity and are enhanced in proteinuric chronic kidney disease, the clinical value of urinary AGT and renin levels during antiproteinuric treatment has yet to be determined. We investigated the clinical usefulness of initial urinary AGT or renin to determine the antiproteinuric effects of angiotensin receptor blockers (ARBs). METHODS: This multicenter, prospective, single-arm study included 205 patients with overt proteinuria (urinary protein/creatinine ratio [uPCR] ≥ 1 mg/mg) enrolled between April 2009 and December 2011. All patients were treated with valsartan. The urinary AGT/creatinine ratio (uAGT/Cr) was measured at the baseline and 24 weeks, and the renin/creatinine ratio (uR/Cr) was measured at the baseline. Fifty-six patients were followed-up for 5 years. RESULTS: The mean age was 47.6 years and 51.2% were male. The mean uPCR was 2.32 mg/mg and the mean eGFR was 63.2 mL/min/1.73m2. Natural logarithms (ln) (uAGT/Cr), ln(uR/Cr), and diabetes mellitus were associated with proteinuria decrement (decrease in uPCR ≥1 mg/mg). Ln(uAGT/Cr) was an independent predictor for proteinuria decrement (OR 1.372, 95% CI, 1.068-1.762, P = 0.013). Among the 56 patients followed-up for 5 years, Δln(uAGT/Cr) at 24 weeks was an independent predictor for uPCR < 1 mg/mg at 5 years (OR 0.379, 95% CI, 0.20-0.715, P = 0.003). CONCLUSIONS: Our study demonstrates the potential role of both baseline urinary AGT and changes in urinary AGT during the initial 24 weeks as surrogate markers predicting the antiproteinuric effects of ARBs in patients with overt proteinuria.

Modeling Uremic Vasculopathy With Induced Pluripotent Stem Cell-Derived Endothelial Cells as a Drug Screening System.

Background: Cardiovascular complications are the leading cause of mortality in patients with chronic kidney disease (CKD). Uremic vasculopathy plays a crucial role in facilitating the progression of cardiovascular complications in advanced CKD. However, the improvement of conventional research methods could provide further insights into CKD. Objectives: In this study, we aimed to develop a novel model of uremic vasculopathy as a potential drug screening system. Methods and Results: The effects of uremic serum and different combinations of uremic toxins on induced pluripotent stem cell (iPSC)-derived endothelial cells (ECs) of a normal control and a CKD patient were investigated using several functional assays. We found that a mixture of uremic toxins composed of high urea, creatinine, uric acid, and indoxyl sulfate exerted deleterious effects on normal control iPSC-ECs that were comparable to uremic serum by increasing reactive oxygen species and apoptosis, as well as suppression of tube formation. Additional characterization revealed a potential involvement of dysregulated TGF-ß signaling as treatment with either losartan or TGF-ß inhibitors led to the attenuation of adverse effects induced by uremic toxins. Importantly, impaired wound healing potential seen in CKD patient-specific iPSC-ECs was rescued by treatment with losartan and TGF-ß inhibitors. Conclusion: Our study demonstrated that simplified uremic toxin mixtures can simulate the uremic micromilieu reproducibly and CKD patient-specific iPSC-ECs can potentially recapitulate susceptibility to uremic vasculopathy. This novel model of uremic vasculopathy may provide a new research tool as a drug screening system.

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.

Effects of percutaneous angioplasty on kidney function and blood pressure in patients with atherosclerotic renal artery stenosis.

BACKGROUND: Previous randomized controlled trials of revascularization for atherosclerotic renal artery stenosis (ARAS) were not successful. We investigated the effects of percutaneous transluminal angioplasty with stent insertion (PTA/S) on kidney function and blood pressure (BP) control in patients with ARAS. METHODS: From 2000 to 2017, 47 subjects who underwent PTA/S for ARAS were identified. A high-risk group was defined, composed of patients having one or more of the following clinical presentations: pulmonary edema, refractory hypertension, and rapid deterioration of kidney function. Subjects who met the criteria of 'kidney function improvement' or 'hypertension improvement' after PTA/S were classified as responders. RESULTS: Twenty-one (44.7%) subjects were classified into the high-risk group. Two subjects (8.0%) in the low-risk group (n = 25) and 5 subjects (27.8%) in the high-risk group (n = 18) showed improvement in kidney function after PTA/S (P = 0.110). In patients with rapid decline of kidney function, estimated glomerular filtration rate improved from 28 (interquartile range [IQR], 10-45) mL/min/1.73 m2 to 41 (IQR, 16-67) mL/min/1.73 m2 at 4 months after PTA/S, although the difference was not significant (P = 0.084). Regarding BP control, 9 (36.0%) and 14 (77.8%) subjects showed improvement after PTA/S in the low- (n = 25) and high-risk (n = 18) groups, respectively (P = 0.007). In patients with refractory hypertension, the systolic BP dropped from 157 (IQR, 150-164) mmHg to 140 (IQR, 131-148) mmHg at 4 months after PTA/S (P = 0.005). Twenty-five subjects were defined as responders and comprised a significant proportion of the high-risk group (P = 0.004). CONCLUSION: PTA/S might improve BP control and kidney function in patients with ARAS presenting with high-risk clinical features. The optimal application of PTA/S should be based on individual assessment of the clinical significance of renal artery stenosis.