Nephrology referral slows the progression of chronic kidney disease, especially among patients with anaemia, diabetes mellitus, or hypoalbuminemia: A single-centre, retrospective cohort study.

BACKGROUND: The Kidney Disease Improving Global Outcomes guidelines recommend nephrology referral for patients with chronic kidney disease (CKD) stages 4 to 5, significant proteinuria and persistent microscopic haematuria. However, the recommendations are opinion-based and which patients with CKD benefit more from nephrology referral has not been elucidated. METHODS: In this retrospective cohort study, patients referred to our nephrology outpatient clinic from April 2017 to March 2019 were included. We excluded patients considered to have an acute decline in kidney function (annual decline in estimated glomerular filtration rate [eGFR] >10 mL/min/1.73 m2). The slopes of eGFR before and after nephrology referral were estimated and compared by linear mixed effects models. Interaction between time and referral status (before or after referral) was assessed and effect modifications by the presence of diabetes, proteinuria (defined by urine dipstick protein 2+ or more), urine occult blood, hypoalbuminemia (defined by albumin levels less than 3.5 g/dL) and anaemia (defined by haemoglobin levels less than 11.0 g/dL) were evaluated. RESULTS: The eGFR slope significantly improved from -2.05 (-2.39 to -1.72) to -0.96 (-1.36 to -0.56) mL/min/1.73 m2/year after nephrology referral (p < .001). The improvement in eGFR slope was more prominent among those with diabetes mellitus, anaemia, and hypoalbuminemia (all p-values for three-way interaction <.001 after adjustment for covariates). Further adjustments for time-dependent haemoglobin levels, the use of erythropoiesis-stimulating agents, iron supplementation, anti-hypertensives and anti-diabetic medications did not change the significance of the interactions. CONCLUSIONS: Nephrology referral slows CKD progression, especially among those with hypoalbuminemia, diabetes or anaemia. Patients with hypoalbuminemia, diabetes or anaemia might benefit more from specialized care and lifestyle modifications by nephrologists. The inclusion of anaemia and hypoalbuminemia in nephrology referral criteria should be considered.

Associations of vitamin D receptor activators and calcimimetics with falls and effect modifications by physical activity: A prospective cohort study on the Japan Dialysis Outcomes and Practice Patterns Study.

INTRODUCTION: This study aimed to examine the associations of vitamin D receptor activators (VDRA) and calcimimetics use with falls. METHODS: This is a prospective cohort study on hemodialysis patients in the Japan Dialysis Outcomes and Practice Patterns Study. We excluded those who were unable to walk. The associations of VDRA or calcimimetics use with falls and effect modifications by physical activity were analyzed using marginal structural models. RESULTS: In total, 1875 patients were included. VDRA and calcimimetics use was not associated with falls (risk ratio [95% CI]: 1.13 [0.84-1.51] and 1.02 [0.72-1.44]). The risk ratio for falls associated with VDRA use was lower among those with poor physical activity (p for interaction <0.1). CONCLUSIONS: Although vitamin D receptor activators and calcimimetics use was not associated with falls, the lower risk ratio for falls with vitamin D receptor activators use among those with poor physical activity suggests that vitamin D receptor activators use might be beneficial among these patients.

Associations of calcium, phosphate and intact parathyroid hormone levels with mortality, residual kidney function and technical failure among patients on peritoneal dialysis.

Background: Associations of calcium, phosphate and intact parathyroid hormone (iPTH) levels with outcomes may be different between patients on peritoneal dialysis (PD) and hemodialysis (HD). The aim of the study is to evaluate these associations among PD patients. Methods: In this prospective cohort study on the Japan Renal Data Registry, adults on PD at the end of 2009 were included. The observation period was until the end of 2018 and the data were censored at the time of transplantation or transition to HD. Exposures were time-averaged or time-dependent albumin-corrected calcium (cCa), phosphate and iPTH levels. Outcomes were all-cause and cardiovascular mortality, transition to HD and urine output. Data were analyzed using Cox regression models or linear mixed-effects models and the results were shown as cubic spline curves. Results: Among 7393 patients, 590 deaths and 211 cardiovascular deaths were observed during a median follow-up of 3.0 years. Higher cCa and phosphate levels were associated with higher mortality. Lower cCa levels were associated with a faster decline, whereas lower phosphate was associated with a slower decline in urine output. Lower phosphate and iPTH levels were associated with a lower incidence of transition to HD. Conclusions: Among PD patients, the observed associations of cCa, phosphate and iPTH with mortality, residual kidney function and technical failure suggest that avoiding high cCa, phosphate and iPTH levels might improve outcomes.

Epidemiology and predictors of hyponatremia in a contemporary cohort of patients with malignancy: a retrospective cohort study.

Background: Hyponatremia is associated with worse outcomes among patients with malignancy. However, contemporary cohort data on epidemiology and risk factors are lacking. Methods: In this single-centre, retrospective cohort study, patients who received intravenous antineoplastic agents from 2018 to 2020 at Nagoya City University Hospital were enrolled. Associations of demographics, antineoplastic agents, types of malignancy and concomitant medications with hyponatremia, defined as serum sodium concentration ≤130 mmol/l, were analysed by mixed-effects logistic regression and the machine learning-based LightGBM model artificial intelligence technology. Results: Among 2644 patients, 657 (24.8%) developed at least one episode of hyponatremia. Approximately 80% of hyponatremia was due to sodium wasting from the kidneys. Variables associated with hyponatremia both by mixed-effects logistic regression and the LightGBM model were older age, hypoalbuminemia and higher estimated glomerular filtration rate. Among antineoplastic agents, cisplatin {odds ratio [OR] 1.52 [95% confidence interval (CI) 1.18-1.96]}, pembrolizumab [OR 1.42 (95% CI 1.02-1.97)] and bortezomib [OR 3.04 (95% CI 1.96-4.71)] were associated with hyponatremia and these variables also had a positive impact on predicted hyponatremia in the LightGBM model. Conclusions: Hyponatremia was common among patients with malignancy. In addition to older age and poor nutritional status, novel antineoplastic agents, including immune checkpoint inhibitors and bortezomib, should be recognized as risk factors for hyponatremia.

The use of anti-adrenergic agents as a predictor of acute kidney injury and delayed recovery of kidney function: the NARA-AKI cohort study.

Association of preoperative regular use of anti-adrenergic agents with postoperative acute kidney injury (AKI) and with trajectory of kidney function after AKI is still unknown. In a retrospective cohort study, adults undergoing non-cardiac surgery under general anesthesia were included. Obstetric or urological surgery, missing data, or preoperative dialysis was excluded. The exposure of interest was preoperative regular use of anti-adrenergic agents. The outcomes were AKI within 1 week postoperatively and trajectories of kidney function within 2 weeks postoperatively among patients with AKI. Multivariable logistic regression models were used to examine the association of anti-adrenergic agents with AKI. Linear mixed-effects models were used to compare the trajectories of postoperative kidney function after AKI between patients with and without anti-adrenergic agents. Among 5168 patients, 245 had used anti-adrenergic agents. A total of 309 (6.0%) developed AKI, and the use of anti-adrenergic agents was independently associated with postoperative AKI even after adjustment for preoperative and intraoperative potential confounders [odds ratio (95% confidence interval): 1.76 (1.14-2.71)]. The association was similar across preexisting hypertension or cardiovascular disease. Analyses restricted to patients with AKI suggested that the timing and stage of AKI were similar among those with and without anti-adrenergic agents; however, the recovery of kidney function was delayed among those with anti-adrenergic agents (P for interaction = 0.004). The use of anti-adrenergic agents was associated with postoperative AKI and delayed recovery of kidney function after AKI. Temporary withdrawal of anti-adrenergic agents during perioperative periods may contribute to prevent AKI and shorten the duration of AKI.

The cisplatin-induced acute kidney injury is a novel risk factor for postoperative complications in patients with esophageal cancer: a retrospective cohort study.

BACKGROUND: Cisplatin-induced acute kidney injury (AKI) is common during preoperative chemotherapy for esophageal cancer. The purpose of this study was to investigate the association between AKI after preoperative chemotherapy and postoperative complications in patients with esophageal cancer. METHODS: In this retrospective cohort study, we included patients who had received preoperative chemotherapy with cisplatin and underwent surgical resection for esophageal cancer under general anesthesia from January 2017 to February 2022 at an education hospital. A predictor was stage 2 or higher cisplatin-induced AKI (c-AKI) defined by the KDIGO criteria within 10 days after chemotherapy. Outcomes were postoperative complications and length of hospital stays. Associations between c-AKI and outcomes including postoperative complications and length of hospital stays were examined with logistic regression models. RESULTS: Among 101 subjects, 22 developed c-AKI with full recovery of the estimated glomerular filtration (eGFR) before surgery. Demographics were not significantly different between patients with and without c-AKI. Patients with c-AKI had significantly longer hospital stays than those without c-AKI [mean (95% confidence interval (95%CI)) 27.6 days (23.3-31.9) and 43.8 days (26.5-61.2), respectively, mean difference (95%CI) 16.2 days (4.4-28.1)]. Those with c-AKI had higher C-reactive protein (CRP) levels and prolonged weight gain after surgery and before the events of interest despite having comparable eGFR trajectories after surgery. c-AKI was significantly associated with anastomotic leakage and postoperative pneumonia [odds ratios (95%CI) 4.14 (1.30-13.18) and 3.87 (1.35-11.0), respectively]. Propensity score adjustment and inverse probability weighing yielded similar results. Mediation analysis showed that a higher incidence of anastomotic leakage in patients with c-AKI was primarily mediated by CRP levels (mediation percentage 48%). CONCLUSION: c-AKI after preoperative chemotherapy in esophageal cancer patients was significantly associated with the development of postoperative complications and led to a resultant longer hospital stay. Increased vascular permeability and tissue edema due to prolonged inflammation might explain the mechanisms for the higher incidence of postoperative complications.

Comparable outcomes between a combination of peritoneal dialysis with once-weekly haemodialysis and thrice-weekly haemodialysis: a prospective cohort study.

BACKGROUND: Outcomes of a combination of peritoneal dialysis (PD) and once-weekly haemodialysis (PD + HD) have not been extensively studied. METHODS: This prospective cohort study using the Japanese Society for Dialysis Therapy Renal Data Registry included those who transitioned from PD to PD + HD therapy or thrice-weekly HD from 2011 to 2018. Exposure was PD + HD therapy compared with thrice-weekly HD. The outcome was time to all-cause or cause-specific death. Associations between PD + HD therapy and outcomes were examined by Cox regression. Sensitivity analyses were performed by propensity score (PS) matching, PS matching with a shared frailty model in which dialysis facilities were treated as a random effect, inverse probability weighting (IPW), PS adjustment, PS stratification, competing risk regression and on-treatment analyses in which data were censored at the transition to thrice-weekly HD for those on PD + HD therapy. RESULTS: During the study period, 1001 subjects transitioned to PD + HD therapy and 2031 to thrice-weekly HD. During a median follow-up of 3.5 years, 575 subjects died. All-cause, cardiovascular, congestive heart failure-related or infection-related mortality were not significantly different between those on PD + HD and those on thrice-weekly HD [hazard ratio 0.95 (95% confidence interval 0.78-1.16), 1.26 (0.92-1.72), 1.24 (0.77-1.99) and 0.89 (0.57-1.39), respectively]. Sensitivity analyses yielded similar results except that PD + HD therapy was associated with significantly lower all-cause mortality by PS adjustment and PS matching with the shared frailty model and lower infection-related mortality by PS adjustment and IPW. CONCLUSIONS: PD + HD therapy was associated with similar or potentially lower mortality compared with thrice-weekly HD. Considering a flexible lifestyle, PD + HD therapy could be a great option.

Kidney function at 3 months after acute kidney injury is an unreliable indicator of subsequent kidney dysfunction: the NARA-AKI Cohort Study.

BACKGROUND: The relationship between kidney function at 3 months after acute kidney injury (AKI) and kidney function prognosis has not been characterized. METHODS: This retrospective cohort study included adults who underwent noncardiac surgery under general anesthesia. Exclusion criteria included obstetric or urological surgery, missing data and preoperative dialysis. Linear mixed-effects models were used to compare estimated glomerular filtration rate (eGFR) slopes in patients with and without AKI. Multivariable Cox proportional hazard models were used to examine the associations of AKI with incident chronic kidney disease (CKD) and decline in eGFR ≥30%. RESULTS: Among 5272 patients, 316 (6.0%) developed AKI. Among 1194 patients with follow-up creatinine values, eGFR was stable or increased in patients with and without AKI at 3 months postoperatively and declined thereafter. eGFR decline after 3 months postoperatively was faster among patients with AKI than among patients without AKI (P = .09). Among 938 patients without CKD-both at baseline and at 3 months postoperatively-226 and 161 developed incident CKD and a decline in eGFR ≥30%, respectively. Despite adjustment for eGFR at 3 months, AKI was associated with incident CKD {hazard ratio [HR] 1.73 [95% confidence interval (CI) 1.06-2.84]} and a decline in eGFR ≥30% [HR 2.41 (95% CI 1.51-3.84)]. CONCLUSIONS: AKI was associated with worse kidney outcomes, regardless of eGFR at 3 months after surgery. Creatinine-based eGFR values at 3 months after AKI might be affected by acute illness-induced loss of muscle mass. Kidney function might be more accurately evaluated much later after surgery or using cystatin C values.

Performance Status Modifies the Association Between Vitamin D Receptor Activator and Mortality or Fracture: A Prospective Cohort Study on the Japanese Society for Dialysis Therapy (JSDT) Renal Data Registry.

Immobilization osteoporosis is characterized by excess bone resorption. Vitamin D receptor activators (VDRA) might have adverse effects in immobilized patients. The objective of this study was to elucidate the impact of performance status (PS) on the associations between VDRA use and outcomes among hemodialysis patients. This is a prospective cohort study. Adults on hemodialysis in the Japanese Society for Dialysis Therapy (JSDT) Renal Data Registry were included. Exposure of interest was the use of VDRA. Outcomes were all-cause mortality and hip fracture. Associations between VDRA use and mortality or hip fractures were examined by Cox and Poisson regression analyses, respectively. Among 208,512 subjects, 128,535 were on VDRA. Poor PS was associated with higher calcium (Ca), lower parathyroid hormone, and higher alkaline phosphatase levels. The association between higher Ca levels and VDRA use was stronger among those with poor PS (p interaction 0.007). Adjusted hazard ratio (HR) (95% confidence interval [CI]) for mortality and incidence rate ratio (IRR) for hip fracture was 1.02 (95% CI, 0.99-1.05) and 0.93 (0.86-1.00) among users of VDRA, respectively. The VDRA use was associated with lower mortality and incidence of hip fractures among subjects with good PS but not among subjects with poor PS (p interaction 0.03 and 0.05). Effect modification by PS was observed for cardiovascular (CV) mortality but not for non-CV mortality. In conclusion, VDRA use was associated with better outcomes only among those with good PS. These results suggest that bone and mineral disorders among hemodialysis patients should be treated differently, depending on their performance status. © 2022 American Society for Bone and Mineral Research (ASBMR).

Sodium-glucose cotransporter 2 inhibitors and anemia among diabetes patients in real clinical practice.

AIMS/INTRODUCTION: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were reported to increase hemoglobin levels in short-term clinical trials. Whether it is also true in real clinical practice is unknown. MATERIALS AND METHODS: This is a retrospective cohort study. Inclusion criterion was diabetes patients who visited our outpatient clinic from January 2019 to August 2020. Exposure of interest was the use of SGLT2i. Outcomes were hemoglobin levels. For the cross-sectional analyses, non-linear regression models were fitted with restricted cubic splines to investigate the association between hemoglobin levels and estimated glomerular filtration rate (eGFR) for users and non-users of SGLT2i. For the case-control study, cases (anemia defined as hemoglobin <120 g/L for men, <110 g/L for women or the use of erythropoiesis stimulating agents) and controls were matched by age, sex and eGFR. RESULTS: Among 2,063 diabetes patients, 723 were taking SGLT2i. In the cross-sectional analyses, hemoglobin levels were higher among SGLT2i users compared with non-users at eGFR >15 mL/min/1.73 m2 . For the case-control study, 197 cases and controls were matched. Conditional logistic regression showed that the use of SGLT2i was associated with significantly lower prevalence of anemia (odd ratio 0.35, 95% confidence interval 0.21-0.58). Adjusted mean differences in hemoglobin levels between users and propensity score-matched non-users of SGLT2i were 7.0 g/L (95% confidence interval 3.0-10.0 g/L) at 6 months. Among SGLT2i users, the odds of an increase in 6-month hemoglobin were similar across eGFR categories, except for eGFR <15 mL/min/1.73 m2 . CONCLUSIONS: The use of SGLT2i was associated with higher hemoglobin levels and lower prevalence of anemia in real clinical practice.

External Validation of a Prediction Model for Acute Kidney Injury Following Noncardiac Surgery.

Importance: The Simple Postoperative AKI Risk (SPARK) index is a prediction model for postoperative acute kidney injury (PO-AKI) in patients undergoing noncardiac surgery. External validation has not been performed. Objective: To externally validate the SPARK index. Design, Setting, and Participants: This single-center retrospective cohort study included adults who underwent noncardiac surgery under general anesthesia from 2007 to 2011. Those with obstetric or urological surgery, estimated glomerular filtration rate (eGFR) of less than 15 mL/min/1.73 m2, preoperative dialysis, or an expected surgical duration of less than 1 hour were excluded. The study was conducted at Nara Medical University Hospital. Data analysis was conducted from January to July 2021. Exposures: Risk factors for AKI included in SPARK index. Main Outcomes And Measures: PO-AKI, defined as an increase in serum creatinine of at least 0.3 mg/dL within 48 hours or 150% compared with preoperative baseline value or urine output of less than 0.5 mL/kg/h for at least 6 hours within 1 week after surgery, and critical AKI, defined as either AKI stage 2 or greater and/or any AKI connected to postoperative death or requiring kidney replacement therapy before discharge. The discrimination and calibration of the SPARK index were examined with area under the receiver operating characteristic curves (AUC) and calibration plots, respectively. Results: Among 5135 participants (2410 [46.9%] men), 303 (5.9%) developed PO-AKI, and 137 (2.7%) developed critical AKI. Compared with the SPARK cohort, participants in our cohort were older (median [IQR] age, 56 [44-66] years vs 63 [50-73] years), had lower baseline eGFR (median [IQR], 82.1 [71.4-95.1] mL/min/1.73 m2 vs 78.2 [65.6-92.2] mL/min/1.73 m2), and had a higher prevalence of comorbidities (eg, diabetes: 3956 of 51 041 [7.8%] vs 802 [15.6%]). The incidence of PO-AKI and critical AKI increased as the scores on the SPARK index increased. For example, 10 of 593 participants (1.7%) in SPARK class A, indicating lowest risk, experienced PO-AKI, while 53 of 332 (16.0%) in SPARK class D, indicating highest risk, experienced PO-AKI. However, AUCs for PO-AKI and critical AKI were 0.67 (95% CI, 0.63-0.70) and 0.62 (95% CI, 0.57-0.67), respectively, and the calibration was poor (PO-AKI: y = 0.24x + 3.28; R2 = 0.86; critical AKI: y = 0.20x + 2.08; R2 = 0.51). Older age, diabetes, expected surgical duration, emergency surgery, renin-angiotensin-aldosterone system blockade use, and hyponatremia were not associated with PO-AKI in our cohort, resulting in overestimation of the predicted probability of AKI in our cohort. Conclusions and Relevance: In this study, the incidence of PO-AKI increased as the scores on the SPARK index increased. However, the predicted probability might not be accurate in cohorts with older patients with more comorbidities.

Combination of once-weekly haemodialysis with peritoneal dialysis is associated with lower mortality compared with peritoneal dialysis alone: a longitudinal study.

BACKGROUND: Approximately 20% of patients on peritoneal dialysis (PD) in Japan are on combination with once-weekly haemodialysis (HD). This study aimed to compare outcomes of combination therapy and PD alone. METHODS: This longitudinal study on the Japanese Renal Data Registry included patients on PD from 2010 to 2014. Subjects were followed until the end of 2015. Exposure of interest was combination therapy compared with PD alone. Outcomes were complete transition to HD, all-cause mortality, cardiovascular (CV) mortality and congestive heart failure (CHF)-related mortality. Patients who initiated combination therapy were matched with those on PD alone by propensity scores. Data were analysed using Cox regression models. RESULTS: Among the matched cohort, 608 patients were on combination therapy and 869 were on PD alone. Decline in body weight and residual renal function was more prominent in the combination therapy group. During a median follow-up of 2.5 years, 224 deaths occurred. All-cause mortality {hazard ratio (HR) [95% confidence interval (CI)] 0.56 (0.42-0.75)}, CV mortality [HR 0.48 (0.32-0.72)] and CHF-related mortality [HR 0.19 (0.07-0.55)] were significantly lower, but complete transition to HD was significantly earlier [HR 1.72 (1.45-2.03)] in the combination therapy group. Sensitivity analyses considering the effects of dialysis facilities yielded similar results. Assuming causality, numbers needed to treat to prevent one death per year were 34 patients. CONCLUSIONS: Combination therapy was associated with lower all-cause mortality, CV mortality and CHF-related mortality, but earlier transition to HD compared with PD alone, which might be due to better fluid removal by HD.

Encapsulating Peritoneal Sclerosis and Mortality Related to Infection in Patients on Combination Once-Weekly Hemodialysis with Peritoneal Dialysis.

INTRODUCTION: Previous studies showed that the combination of peritoneal dialysis (PD) and once-weekly hemodialysis is associated with lower all-cause and cardiovascular mortality. This study aimed to compare the incidence of encapsulating peritoneal sclerosis (EPS) and infection-related mortality among those on combination therapy and those on PD alone. METHODS: This prospective study on the Japanese Renal Data Registry included patients on PD from 2010 to 2014. Subjects were followed up until the end of 2015. Exposure of interest was combination therapy compared with PD alone. Patients who transitioned to combination therapy were matched with those on PD alone by propensity scores. Outcomes were EPS and infection-related mortality. Data were analyzed using Cox regression models. RESULTS: Among the matched cohort, 608 and 869 patients were on combination therapy and on PD alone, respectively. Dialysate-to-plasma creatinine (D/P Cr) ratio decreased over time among those on combination therapy, while the ratio increased among those on PD alone (p = 0.01 by the mixed-effects model). During a median follow-up of 2.5 years, 33 experienced EPS and 55 died of infection. Combination therapy was associated with lower infection-related mortality (HR [95% CI]: 0.52 [0.28-0.95]) but not with EPS (HR: 1.21 [0.61-2.40]). Lower mortality was not limited to intra-abdominal infection but also observed for pulmonary infection. Sensitivity analyses considering the effects of dialysis facilities yielded similar results. CONCLUSIONS: Combination therapy was associated with lower infection-related mortality. It was also associated with a decline in the D/P Cr ratio over time but not with lower incidence of EPS during the short observation period.

Impact of self-reported walking habit on slower decline in renal function among the general population in a longitudinal study: the Japan Specific Health Checkups (J-SHC) Study.

BACKGROUND: Association between physical activity and decline in renal function among the general population is not fully understood. METHODS: This is a longitudinal study on subjects who participated in the Japanese nationwide Specific Health Checkup program between 2008 and 2014. The exposure of interest was baseline self-reported walking habit. The outcomes were annual change and incidence of 30% decline in estimated glomerular filtration rate (eGFR). Changes in eGFR were compared using a linear mixed-effects model. Cox proportional hazard models were used to examine the association between self-reported walking habit and 30% decline in eGFR. RESULTS: Among 332,166 subjects, 168,574 reported walking habit at baseline. The annual changes in eGFR [95% confidence interval (CI)] among subjects with and without baseline self-reported walking habit were - 0.17 (- 0.19 to - 0.16) and - 0.26 (- 0.27 to - 0.24) mL/min/1.73 m2/year, respectively (P for interaction between time and baseline self-reported walking habit, < 0.001). During a median follow-up of 3.3 years, 9166 of 314,489 subjects exhibited 30% decline in eGFR. The incidence of 30% decline in eGFR was significantly lower among subjects with self-reported walking habit after adjustment for potential confounders including time-varying blood pressure, body mass index, lipid profile, and hemoglobin A1c, with hazard ratio (95% CI) of 0.93 (0.89-0.97). Sensitivity analysis restricted to subjects with unchanged self-reported walking habit from baseline or analysis with time-varying self-reported walking habit yielded similar results. CONCLUSIONS: Self-reported walking habit was associated with significantly slower decline in eGFR. This association appeared to be independent of its effects on metabolic improvement.

Anemia following acute kidney injury after noncardiac surgery and long-term outcomes: the NARA-AKI cohort study.

Background: This study was conducted to investigate whether acute kidney injury (AKI) is an independent predictor of anemia and whether anemia following AKI is a mediator of mortality after AKI. Methods: This is a retrospective cohort study. Adults with noncardiac surgery from 2007 to 2011 were included. Obstetric or urological surgery, missing data or preoperative dialysis were excluded. Subjects were followed until the end of 2015 or lost to follow-up. Exposures of interest were postoperative AKI. Outcome variables were hematocrit values at 3, 6 and 12 months postoperatively and mortality. Associations between AKI and hematocrit or association between AKI and mortality were examined by multivariable linear regression or Cox regression, respectively. Results: Among 6692 subjects, 445 (6.6%) developed AKI. Among those with postoperative data, AKI was independently associated with lower hematocrit at 3, 6 and 12 months postoperatively, with coefficients of -0.79 [95% confidence interval (CI) -1.47 to -0.11; n = 1750], -1.35 (-2.11 to -0.60; n = 1558) and -0.91 (-1.59 to -0.22; n = 2463), respectively. Higher stages or longer duration of AKI were associated with more severe anemia. AKI was associated with higher mortality after 3 months postoperatively with a hazard ratio of 1.54 (95% CI 1.12-2.12). Further adjustment with hematocrit at 3 months attenuated the association. The mediation effect was significant (P = 0.02) by mediation analysis. Conclusions: AKI was an independent predictor of anemia following AKI. Higher mortality associated with AKI was at least partially mediated by anemia following AKI. Whether correction of anemia following AKI improves mortality requires further research.

Pre-operative proteinuria and post-operative acute kidney injury in noncardiac surgery: the NARA-Acute Kidney Injury cohort study.

BACKGROUND: Little is known about the association between pre-operative proteinuria and post-operative acute kidney injury (AKI) in noncardiac surgery. METHODS: This is a retrospective cohort study. Adults who underwent noncardiac surgery under general anesthesia from 2007 to 2011 at Nara Medical University Hospital were included. Those with obstetric or urological surgery, missing data for analyses or pre-operative dialysis were excluded. Exposure of interest was pre-operative proteinuria, defined as (+) or more by dipstick test. The outcome variable was post-operative AKI, defined by Kidney Disease: Improving Global Outcomes criteria, within 1 week after surgery. Multivariable logistic regression analyses were performed. RESULTS: Among 5168 subjects, 309 (6.0%) developed AKI. Pre-operative proteinuria was independently associated with post-operative AKI, with an odds ratio (OR) [95% confidence interval (CI)] of 1.80 (1.30-2.51). A sensitivity analysis restricted to elective surgery yielded a similar result. As proteinuria increased, the association with AKI became stronger [OR (95% CI) 1.14 (0.75-1.73), 1.24 (0.79-1.95), 2.75 (1.74-4.35) and 3.95 (1.62-9.62) for urinary protein (+/-), (+), (2+) and (3+), respectively]. Subgroup analyses showed proteinuria was especially associated with post-operative AKI among subjects with renin-angiotensin system inhibitors, other anti-hypertensives, hypoalbuminemia or impaired renal function (P for interaction = 0.05, 0.003, 0.09 or 0.02, respectively). CONCLUSIONS: In noncardiac surgery, pre-operative proteinuria was independently associated with post-operative AKI. Subjects with proteinuria should be managed with caution to avoid AKI peri-operatively.

Positive association between intra-operative fluid balance and post-operative acute kidney injury in non-cardiac surgery: the NARA-AKI cohort study.

BACKGROUND: Little is known about the association between intra-operative fluid balance (IFB) and post-operative acute kidney injury (AKI) in non-cardiac surgery. METHODS: This is a retrospective cohort study. Adults who underwent non-cardiac surgery under general anesthesia from 2007 to 2011 at Nara Medical University Hospital were included. Those with obstetric or urological surgery, missing data, or pre-operative dialysis were excluded. Exposure of interest was IFB, defined as (amount of fluid administration - urine output - amount of bleeding)/body weight. Outcome variable was post-operative AKI within 1 week after surgery. Data were analyzed using logistic regression models and restricted cubic spline (RCS) analysis. RESULTS: Among 5168 subjects, AKI was observed in 309 (6.0%). Higher IFB (per 1 standard deviation) was independently associated with post-operative AKI after adjustment for potential confounders (odds ratio [95% confidence interval] of 1.18 [1.06-1.31]). The RCS curve showed an increase in expected probability of AKI associated with increase in IFB above 40 mL/kg. Subgroup analyses indicated higher IFB was especially associated with AKI among those with lower serum albumin, higher C-reactive protein, or positive proteinuria. The association was similar across intra-operative urine output or amount of bleeding (p for interaction 0.34 and 0.47, respectively), suggesting the association was not due to intra-operative oliguria or large amount of bleeding necessitating volume resuscitation. CONCLUSIONS: Higher IFB was independently associated with increase in post-operative AKI. Excessive fluid administration might have caused renal congestion and subsequent AKI. Avoiding fluid overload might be important in prevention of AKI.

Inflammation as a predictor of acute kidney injury and mediator of higher mortality after acute kidney injury in non-cardiac surgery.

This retrospective cohort study examined the roles of inflammation in acute kidney injury (AKI). Serum albumin and C-reactive protein (CRP) were used as markers of inflammation. Adults who underwent non-cardiac surgery from 2007 to 2011 were included. Exclusion criteria were urological surgery, obstetric surgery, missing data, and pre-operative dialysis. Subjects were followed until the end of 2015 or loss to follow-up. Associations between pre-operative albumin or CRP and post-operative AKI or association between AKI and mortality were examined by logistic or Cox regression, respectively. Mediation analyses were performed using albumin and CRP as mediators. Among 4,538 subjects, 272 developed AKI. Pre-operative albumin was independently associated with AKI (odds ratio [95% confidence interval (CI)]: 0.63 [0.48-0.83]). During a median follow-up of 4.5 years, 649 died. AKI was significantly associated with mortality (hazard ratio [HR] [95% CI]: 1.58 [1.22-2.04]). Further adjustment for pre-operative albumin and CRP attenuated the association (HR [95% CI]: 1.28 [0.99-1.67]). The proportions explained by mediating effects of lnCRP and albumin were 29.3% and 39.2% and mediation effects were statistically significant. In conclusion, inflammation is a predictor of AKI and a mediator of mortality after AKI. Interventions targeting inflammation might improve outcomes of AKI.

Effect of darbepoetin alfa on endothelial progenitor cells and vascular reactivity in chronic kidney disease.

Endothelial progenitor cells (EPCs) are thought to be important for maintaining normal vascular function. We conducted a prospective study evaluating the effect of the erythropoiesis-stimulating agent darbepoetin alfa on EPCs and vascular function in patients with chronic kidney disease (CKD), with or without diabetes. Thirty subjects with CKD (20 subjects with type II diabetes mellitus and 10 without diabetes mellitus) received weekly subcutaneous administration of darbepoetin alfa for 4 weeks. EPCs were measured at baseline and 2 and 4 weeks after drug administration. Vascular function was measured with brachial ultrasound and cell activity was measured with a cell proliferation assay. Cells expressing CD133, CD34, CD146 and CD146/31 were significantly elevated (all p < 0.05), flow-mediated vasodilatation increased 2.1%, 95% CI: (0.4%, 3.8%) and colony-forming units increased twofold, 95% CI: (1.7, 2.3) after 4 weeks of treatment with darbepoetin alfa. Subjects with diabetes exhibited an increase in a subset of EPCs (CD133( +) and 34(+), p < 0.01 and p = 0.06, respectively), vasodilatation and proliferation. In conclusion, the administration of darbepoetin alfa for 4 weeks increased a subset of EPCs, improved endothelial function and increased cell proliferation, including those with diabetes, which is consistent with a favorable improvement in vascular health.