Low-Dose Continuous Kidney Replacement Therapy and Mortality in Critically Ill Patients With Acute Kidney Injury: A Retrospective Cohort Study.

RATIONALE & OBJECTIVE: Continuous kidney replacement therapy (CKRT) is preferred when available for hemodynamically unstable acute kidney injury (AKI) patients in the intensive care unit (ICU). The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend a delivered CKRT dose of 20-25mL/kg/h; however, in Japan the doses are typically below this recommendation due to government health insurance system restrictions. This study investigated the association between mortality and dose of CKRT. STUDY DESIGN: Single-center retrospective cohort study. SETTING & PARTICIPANTS: Critically ill patients with AKI treated with CKRT at a tertiary Japanese university hospital between January 1, 2012, and December 31, 2021. EXPOSURE: Delivered CKRT doses below or above the median. OUTCOME: 90-day mortality after CKRT initiation. ANALYTICAL APPROACH: Multivariable Cox regression analysis and Kaplan-Meier analysis. RESULTS: The study population consisted of 494 patients. The median age was 72 years, and 309 patients (62.6%) were men. Acute tubular injury was the leading cause of AKI, accounting for 81.8%. The median delivered CKRT dose was 13.2mL/kg/h. Among the study participants, 456 (92.3%) received delivered CKRT doses below 20mL/kg/h, and 204 (41.3%) died within 90 days after CKRT initiation. Multivariable Cox regression analysis revealed increased mortality in the below-median group (HR, 1.73 [95% CI, 1.19-2.51], P=0.004). Additionally, a significant, inverse, nonlinear association between 90-day mortality and delivered CKRT dose was observed using delivered CKRT dose as a continuous variable. LIMITATIONS: Single-center, retrospective, observational study. CONCLUSIONS: A lower delivered CKRT dose was independently associated with higher 90-day mortality among critically ill patients who mostly received dosing below the current KDIGO recommendations. PLAIN-LANGUAGE SUMMARY: The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend delivering a continuous kidney replacement therapy (CKRT) dose of 20-25mL/kg/h. However, it is not clear if it is safe to use delivered CKRT doses below this recommendation. In this study, over 90% of the patients received CKRT with a delivered dose below the KDIGO recommendation. We divided these patients into 2 groups based on the median delivered CKRT dose. Our findings show that a delivered CKRT dose below the median was associated with increased risk of death within 90 days. These findings show that a lower delivered CKRT dose was independently associated with higher 90-day mortality among critically ill patients who mostly received dosing below current KDIGO recommendations.

Factors affecting the sodium-glucose cotransporter 2 inhibitors-related initial decline in glomerular filtration rate and its possible effect on kidney outcome in chronic kidney disease with type 2 diabetes: The Japan Chronic Kidney Disease Database.

AIM: Sodium-glucose cotransporter 2 (SGLT2) inhibitors often cause a transient decrease in glomerular filtration rate (GFR) shortly after the initiation, referred to as the 'initial drop'. However, the clinical significance of this initial drop in real-world practice remains unclear. MATERIALS AND METHODS: Using the nationwide Japan Chronic Kidney Disease Database, we examined factors that affected the initial drop, in patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). We also evaluated the effects of the initial drop on a composite kidney outcome (a decline in GFR of ≥50% or progression to end-stage kidney disease). RESULTS: Data from 2053 patients with CKD and T2DM newly prescribed an SGLT2 inhibitor were analysed. The follow-up period after SGLT2 inhibitor administration was 1015 days (interquartile range: 532, 1678). Multivariate linear regression models revealed that the concomitant use of the renin-angiotensin system inhibitors and diuretics, urinary protein levels ≥2+, and changes in GFR before the initiation of the SGLT2 inhibitor were associated with a larger initial GFR decline (ß = -0.609, p = .039; ß = -2.298, p < .001; ß = -0.936, p = .048; ß = -0.079, p < .001, respectively). Patients in the quartile with the largest initial GFR decline experienced a higher incidence of the subsequent composite kidney outcome than those in the other quartiles (p < .001). CONCLUSIONS: The concomitant use of renin-angiotensin system inhibitors and diuretics, higher urine protein levels and pre-treatment GFR changes were associated with a larger initial GFR decline. Of these factors, the use of a diuretic had the largest effect. Furthermore, patients with CKD and T2DM experiencing an excessive initial GFR drop might be at a higher risk of adverse kidney outcomes.

History of fragility fracture is associated with cardiovascular mortality in hemodialysis patients: the Q-Cohort study.

INTRODUCTION: In patients undergoing dialysis, major bone fracture is associated with a high risk of mortality, including death of cardiovascular (CV) origin. In the present study, we aimed to determine whether a history of fragility fracture is a predictor of CV death in patients undergoing hemodialysis with long-term follow-up. MATERIALS AND METHODS: In total, 3499 patients undergoing hemodialysis were analyzed for 10 years. We evaluated the history of fragility fracture in each patient at enrollment. The primary outcome was CV death. A Cox proportional hazard model and a competing risk approach were applied to determine the association between a history of fragility fracture and CV death. RESULTS: A total of 346 patients had a history of fragility fracture at enrollment. During a median follow-up of 8.8 years, 1730 (49.4%) patients died. Among them, 621 patients experienced CV death. Multivariable Cox analyses after adjustment for confounding variables showed that a history of fragility fracture was associated with CV death (hazard ratio, 1.47; 95% confidence interval, 1.16-1.85). In the Fine-Gray regression model, a history of fragility fracture was an independent risk factor for CV death (subdistribution hazard ratio, 1.36; 95% confidence interval, 1.07-1.72). CONCLUSION: In a large cohort of patients undergoing hemodialysis, a history of fragility fracture was an independent predictor of CV death.

Cigarette smoking and progression of kidney dysfunction: a longitudinal cohort study.

INTRODUCTION: Cigarette smoking is one of the most important life-modifiable risk factors for CVD events. The effect on CKD progression caused by smoking remained uncertain, while the effect on CVD had been established. METHOD: The study population included participants from the specific health check and specific health guidance, an annual health check-up for all inhabitants of Japan who were aged between 40 and 74 years. 149,260 subjects (male, 37.1%; female, 62.9%) were included in this analysis. RESULTS: The relationship between smoking status along with new-onset proteinuria and eGFR deterioration more than 15 mL/min/1.73 m2 was examined. Median observation periods were 1427 days [738, 1813] in males and 1437 days [729, 1816] in females. In male participants, the strongest factor upon kidney dysfunction was new-onset proteinuria (1.41 [1.31 1.51], P < 0.001). The second strongest factor on kidney deterioration was smoking (1.24 [1.16 1.31], P < 0.001). In female participants, strongest factor upon kidney dysfunction was smoking (1.27 [1.16-1.39], P < 0.001). The second strongest factor on kidney deterioration was new-onset proteinuria (1.26 [1.17 1.36], P < 0.001). To reveal the relationship of effects from new-onset proteinuria and smoking on the kidney function, the participants were divided into four groups with and without new-onset proteinuria and smoking. The group with both proteinuria and smoking had significantly worst renal prognosis (P for trend < 0.001). CONCLUSION: Large longitudinal observation study revealed smoking has an evil effect on the progression of CKD. This evil effect could be observed in CKD patients with proteinuria as well as in general population without new-onset proteinuria.

Cognitive Impairment and Brain Atrophy in Patients with Chronic Kidney Disease.

In Japan, the aging of the population is rapidly accelerating, with an increase in patients with chronic kidney disease (CKD) and those undergoing dialysis. As a result, the number of individuals with cognitive impairment (CI) is rising, and addressing this issue has become an urgent problem. A notable feature of dementia in CKD patients is the high frequency of vascular dementia, making its prevention through the management of classical risk factors such as hypertension, diabetes mellitus, dyslipidemia, smoking, etc., associated with atherosclerosis and arteriosclerosis. Other effective measures, including the use of renin-angiotensin system inhibitors, addressing anemia, exercise therapy, and lifestyle improvements, have been reported. The incidence and progression of CI may also be influenced by the type of kidney replacement therapy, with reports suggesting that long-duration dialysis, low-temperature hemodialysis, peritoneal dialysis, and kidney transplantation can have a preferable effect on the preservation of cognitive function. In conclusion, patients with CKD are at a higher risk of developing CI, with brain atrophy being a contributing factor. Despite the identification of various preventive measures, the evidence substantiating their efficacy remains limited across all studies. Future expectations lie in large-scale randomized controlled trials.

Impact of Age on Prescribing Patterns of Cardiovascular Medications in Older Japanese Patients with Non-Dialysis-Dependent Chronic Kidney Disease: A Cross-Sectional Study.

AIM: Older patients with chronic kidney disease (CKD) are more likely to be excluded from clinical trials. This exclusion affects the quality of cardiovascular disease (CVD) prevention in this population. METHODS: Baseline data from the Fukuoka Kidney Disease Registry (FKR) cohort, which included 4476 adult patients with CKD stages G1-G5, were cross-sectionally analyzed to compare the use of recommended drugs for preventing CVD in each age group. RESULTS: Different prescribing patterns were observed according to age for the cardiovascular drug classes. Older patients with CKD were less likely to receive renin-angiotensin system (RAS) inhibitors and were more likely to receive calcium channel blockers. The proportion of anticoagulation prescriptions for patients with CKD and atrial fibrillation decreased in the older age group (≥ 75 years). However, the proportion of antiplatelet therapy in patients with ischemic CVD increased linearly with age, even in the very old group aged ≥ 85 years. These findings suggest a severe cardiovascular burden in patients with CKD. Notably, RAS inhibitor use was avoided in the older group despite a severe cardiovascular burden, such as a high prevalence of CVD history and massive albuminuria ＞300 mg/g creatinine. This finding indicates that an older age independently contributed to the non-use of RAS inhibitors, even after adjusting for other covariates. CONCLUSIONS: This study suggests that age is a potential barrier to the treatment of patients with CKD and highlights the need to establish individualized treatment strategies for cardiovascular protection in this population.

Management of anaemia and prognosis of patients undergoing maintenance peritoneal dialysis: A nationwide cohort study.

BACKGROUND: Clinical data supporting the target haemoglobin range in patients undergoing peritoneal dialysis (PD) are scarce. This study investigated the association between haemoglobin levels and all-cause mortality in Japanese patients undergoing PD using data from a nationwide dialysis registry. METHODS: A total of 4875 patients aged ≥18 years who were undergoing PD at the end of 2012 were analysed. Patients receiving combination therapy with haemodialysis or missing haemoglobin data were excluded. Haemoglobin values were categorised into six groups (<9.0, 9.0-9.9, 10.0-10.9, 11.0-11.9, 12.0-12.9 and ≥13.0 g/dL) and their association with mortality evaluated. RESULTS: Patients' mean age was 63 years, and 62% were men. The mean haemoglobin level was 10.7 g/dL, and 14% were anuric. Erythropoiesis-stimulating agents were used in 89%. During a median follow-up of 3.5 years, 1586 patients died. Haemoglobin levels <9.0 and ≥13.0 g/dL were significantly associated with mortality, as compared with levels of 10.0-10.9 g/dL (adjusted hazard ratios [95% confidence intervals]: 1.25 [1.06-1.48] and 1.45 [1.13-1.88], respectively). Restricted cubic spline analysis revealed a U-shaped association between haemoglobin levels and mortality. A haemoglobin level ≥12 g/dL was associated with mortality in patients with a history of cardiovascular disease (p interaction = 0.023). CONCLUSION: We provide important insights into the target haemoglobin in patients undergoing PD. Our findings suggest that setting a lower upper limit for haemoglobin levels may be beneficial for patients with a history of cardiovascular disease.

Disturbance in the potential cardiovascular-bone-skeletal muscle axis and morbidity and mortality in patients undergoing haemodialysis: the Q-Cohort Study.

Background: Disturbances in the cardiovascular system, bone and skeletal muscle are independent risk factors for death among patients receiving haemodialysis (HD). However, the combined impact of disorders of these three organs on morbidity and mortality is unclear in the HD population. Methods: A total of 3031 Japanese patients on maintenance HD were prospectively followed. The outcomes were all-cause mortality, major adverse cardiovascular events (MACE) and bone fracture. Patients were divided into four groups (G1-G4) according to the baseline number of diseased organs represented as histories of cardiovascular disease and bone fractures and the presence of low skeletal muscle mass as follows: G1, no organ; G2, one organ; G3, two organs; G4, three organs. Multivariable-adjusted survival models were used to analyse associations between the number of diseased organs and outcomes. Results: During a 4-year follow-up, 499 deaths, 540 MACE and 140 bone fractures occurred. In the Cox proportional hazards model, the risk for all-cause mortality was significantly higher in G2, G3 and G4 than in G1 as the reference {hazard ratio: G2, 2.16 [95% confidence interval (CI) 1.65-2.84], G3, 3.10 [95% CI 2.27-4.23] and G4, 3.11 [95% CI 1.89-5.14]}. Similarly, the risks for developing MACE and bone fractures were significantly elevated as the number of organ disorders increased. Conclusions: Multiple disorders of the cardiovascular-bone-skeletal muscle axis are strong predictors of morbidity and mortality in patients undergoing HD.

Associations between the Serum Triglyceride Level and Kidney Outcome in Patients with Chronic Kidney Disease: The Fukuoka Kidney disease Registry Study.

AIMS: Hypertriglyceridemia is a risk factor for chronic kidney disease (CKD). However, whether or not it predicts the risk of CKD progression is unknown. This study evaluated the association between serum triglyceride (TG) levels and kidney disease progression in patients with non-dialysis-dependent CKD. METHODS: The Fukuoka Kidney disease Registry (FKR) study was a multicenter, prospective longitudinal cohort study. In total, 4,100 patients with CKD were followed up for 5 years. The primary outcome was the incidence of CKD progression, defined as a ≥ 1.5-fold increase in serum creatinine level or the development of end-stage kidney disease. The patients were divided into quartiles according to baseline serum TG levels under non-fasting conditions: Q1 ＜87 mg/dL; Q2, 87-120 mg/dL; Q3, 121-170 mg/dL, and Q4 ＞170 mg/dL. RESULTS: During the 5-year observation period, 1,410 patients met the criteria for CKD progression. The multivariable-adjusted Cox proportional hazards model showed a significant association between high serum TG level and the risk of CKD progression in the model without macroalbuminuria as a covariate (multivariable hazard ratio[HR] for Q4 versus Q1, 1.20; 95% CI, 1.03-1.41; P=0.022), but the significance disappeared after adjusting for macroalbuminuria (HR for Q4 versus Q1, 1.06; 95% CI, 0.90-1.24; P=0.507). CONCLUSIONS: The present findings suggest that individuals with high serum TG levels are more likely to develop CKD progression than those without; however, whether or not higher serum TG levels reflect elevated macroalbuminuria or lead to CKD progression via elevated macroalbuminuria is unclear.

Relationships of Weight Change from 20 Years of Age with the Risks of All-Cause and Cardiovascular Mortality in Patients with Chronic Kidney Disease.

AIMS: Weight changes from a young age are known to be associated with poor life outcomes in the general population. However, little is known about the association between weight change from a young age and life expectancy in patients with chronic kidney disease (CKD). METHODS: Data of 2,806 nondialysis CKD patients who participated in the Fukuoka Kidney Disease Registry (FKR) Study, a multicenter observational study, were analyzed. The primary outcome was all-cause death, whereas the secondary outcome was cardiovascular mortality. The covariate of interest was weight change, defined as the difference between body weight at study enrollment and at 20 years old. Cox proportional-hazards models were used to estimate the risks of mortality for participants with weight changes of ≥ 5 or ＜5 kg compared with those with stable weights. RESULTS: During the 5-year observation period, 243 participants died from all causes and 62 from cardiovascular disease. The risk of all-cause mortality in the weight-loss group was significantly higher than that in the stable-weight group (multivariable-adjusted hazard ratio, 2.11; 95% confidence interval [CI], 1.52-2.93). Conversely, the risk of cardiovascular mortality in the weight-loss group was significantly higher than that in the stable-weight group (multivariable-adjusted hazard ratio, 2.48; 95% CI, 1.32-4.64). However, no significant association was observed between weight gain and the risks of all-cause and cardiovascular mortalities. CONCLUSION: Weight loss from 20 years of age was found to be associated with higher risks of all-cause and cardiovascular mortalities in patients with CKD.

More rapid progression of brain atrophy in patients on peritoneal dialysis compared with hemodialysis: The VCOHP Study.

We previously reported that brain atrophy was more severe and progressed more rapidly in patients with end-stage kidney disease on peritoneal dialysis (PD) than those with non-dialysis-dependent chronic kidney disease. However, it remains unknown whether there is a difference between patients on PD and hemodialysis (HD). In total, 73 PD and 34 HD patients who underwent brain magnetic resonance imaging (MRI) were recruited for a cross-sectional analysis. Among them, 42 PD and 25 HD patients who underwent a second brain MRI after 2 years were recruited for a longitudinal analysis. T1-weighted MRI images were analyzed. Total gray matter volume (GMV), total white matter volume, and cerebrospinal fluid volume were segmented, and each volume was quantified using statistical parametric mapping software. The ratio of GMV (GMR) was calculated by dividing GMV by intracranial volume, to adjust for variations in head size. We compared GMR between PD and HD patients in the cross-sectional analysis and the annual change in GMR (AC-GMR) in the longitudinal analysis. In the cross-sectional analysis, age- and sex-adjusted GMR was significantly lower in PD than HD patients [least square mean (LSM): 39.2% vs. 40.0%, P = 0.018]. AC-GMR was significantly greater in PD than HD patients and this difference remained significant even after adjustment for potential confounding factors (LSM: -0.68 vs. -0.28 percentage-points/year, P = 0.011). In conclusion, the present study demonstrated a more rapid progression of brain atrophy in PD patients compared with HD patients. We demonstrated that decline in GMR progressed significantly more rapidly in PD than HD patients independent of potential confounding factors. GMR gray matter volume ratio, HD hemodialysis, PD peritoneal dialysis.

Blood Hemoglobin Concentrations and the Incidence of Lower Extremity Peripheral Arterial Disease in Patients Undergoing Hemodialysis: 10-Year Outcomes of the Q-Cohort Study.

BACKGROUND: Lower extremity peripheral arterial disease is a potentially lethal cardiovascular complication in patients undergoing hemodialysis. Anemia is a risk factor for cardiovascular disease among the hemodialysis population. However, whether blood hemoglobin concentration is associated with the risk of peripheral arterial disease progression in this population remains undetermined. METHODS AND RESULTS: This is an extension of a 4-year multicenter, prospective, observational cohort study to 10 years. A total of 3504 Japanese patients undergoing maintenance hemodialysis were recruited between 2006 and 2007. The primary exposure was blood hemoglobin concentration at baseline. The main outcome was the first-ever incidence of major adverse limb events (MALE), composed of endovascular treatment, bypass surgery, and amputation. Multivariable-adjusted Cox proportional hazards model, Fine-Gray subdistribution hazards model, restricted cubic spline analysis, and restricted mean survival time analysis were used to determine the association of blood hemoglobin concentration with the incidence of MALE. During a median follow-up of 8.0 years, 257 patients experienced MALE. A Cox proportional hazards model showed that the risk of MALE in patients with blood hemoglobin concentrations <10.0 g/dL was significantly higher than in patients with concentrations of 11.0 to 11.9 g/dL, even after adjusting for confounding factors. In contrast, elevated hemoglobin concentration (≥12.0 g/dL) was not significantly associated with increased risk of MALE. Similar associations were observed when the Fine-Gray subdistribution regression model was used by setting all-cause mortality as the competing risk. CONCLUSIONS: A low blood hemoglobin concentration is an independent risk factor for peripheral arterial disease progression in patients undergoing maintenance hemodialysis.

Identification of three distinct cell populations for urate excretion in human kidneys.

In humans, uric acid is an end-product of purine metabolism. Urate excretion from the human kidney is tightly regulated by reabsorption and secretion. At least eleven genes have been identified as human renal urate transporters. However, it remains unclear whether all renal tubular cells express the same set of urate transporters. Here, we show renal tubular cells are divided into three distinct cell populations for urate handling. Analysis of healthy human kidneys at single-cell resolution revealed that not all tubular cells expressed the same set of urate transporters. Only 32% of tubular cells were related to both reabsorption and secretion, while the remaining tubular cells were related to either reabsorption or secretion at 5% and 63%, respectively. These results provide physiological insight into the molecular function of the transporters and renal urate handling on single-cell units. Our findings suggest that three different cell populations cooperate to regulate urate excretion from the human kidney, and our proposed framework is a step forward in broadening the view from the molecular to the cellular level of transport capacity.

Pulse pressure modifies the association between diastolic blood pressure and decrease in kidney function: the Japan Specific Health Checkups Study.

Background: Unlike systolic blood pressure (SBP), the prognostic value of diastolic blood pressure (DBP) in kidney function has not been established. We hypothesized that pulse pressure (PP), which is associated with arteriosclerosis, would affect the prognostic value of DBP. Methods: This longitudinal study used data from the Japan Specific Health Checkups Study was conducted between 2008 and 2014. The participants were stratified into three PP subgroups (low PP ≤39, normal PP 40-59 and high PP ≥60 mmHg). The exposures of interest were SBP and DBP, and the association between SBP/DBP and kidney outcomes (30% decline in the estimated glomerular filtration rate from baseline) was examined in each PP subgroup using a Cox proportional hazards model. Results: Among 725 022 participants, 20 414 (2.8%) developed kidney outcomes during a median follow-up period of 34.6 months. Higher SBP was consistently associated with a higher incidence of kidney outcome in all PP subgroups. Although DBP had a positive linear association with the incidence of kidney outcome in low- and normal-PP subgroups, both lower (≤60 mmHg) and higher (≥101 mmHg) DBP were associated with a higher incidence of kidney outcome in the high-PP subgroup, with a U-shaped curve. Hazard ratios (95% confidence intervals) of ≤60 mmHg (reference: 61-80 mmHg in normal-PP subgroup) and ≥101 mmHg were 1.26 (1.15-1.38) and 1.86 (1.62-2.14), respectively. Conclusions: In this large population-based cohort, DBP was differently associated with kidney outcome by PP level; lower DBP was significantly associated with a higher incidence of kidney outcome in the high-PP subgroup but not in the low- and normal-PP subgroups.

Evaluating the associations between compliance with CKD guideline component metrics and renal outcomes.

Understanding the association between compliance to the Chronic Kidney Disease (CKD) guidelines in real-world clinical settings and renal outcomes remains a critical gap in knowledge. A comprehensive analysis was conducted using data from a national, multicenter CKD registry. This study included 4,455 patients with an estimated glomerular filtration rate (eGFR) measurement on the index date and eight additional metrics recorded within six months. These metrics comprised serum electrolyte levels, low-density lipoprotein cholesterol, hemoglobin, and the use of renin-angiotensin system inhibitors. The primary outcome was a composite of renal events, defined by a decline in eGFR to < 15 mL/min/1.73 m2 or a reduction of ≥ 30% in eGFR, confirmed by follow-up tests. Over a median follow-up of 513 days, 838 renal events were observed. High serum potassium levels (> 5.4 mmol/L) were associated with increased event rates compared to lower levels. Similarly, low serum sodium-chloride levels (< 33) correlated with higher event rates. Usage of renin-angiotensin system inhibitors, low serum calcium (< 8.4 mg/dL), and high uric acid levels (> 7.0 mg/dL) were also linked to increased events. Conversely, higher hemoglobin levels (≥ 13 g/dL) were associated with lower event rates. Compliance to guidelines, categorized into quartiles based on the number of met metrics, revealed a significantly reduced risk of events in the highest compliance group (meeting 8 metrics) compared to the lowest (0-5 metrics). Compliance to CKD guidelines in clinical practice is significantly associated with improved renal outcomes, emphasizing the need for guideline-concordant care in the management of CKD.