Prognostic factors for acute ischemic stroke in patients undergoing hemodialysis.

BACKGROUND: Acute ischemic stroke (AIS) is a critical complication in patients undergoing dialysis. Although the improvement of AIS management is an urgent requirement, few studies have evaluated the prognostic factors of AIS in these patients. This study aimed to assess the relationship between clinical factors in patients undergoing dialysis and the prognosis of AIS. METHODS: Among 1267 patients who were hospitalized for AIS in Sendai City Hospital from January 2015 to June 2020, 81 patients undergoing hemodialysis were retrospectively enrolled. Multivariate analysis was performed to evaluate the effect of baseline characteristics, dialysis factors, and neurological severity of patients at admission [National Institutes of Health Stroke Scale (NIHSS) score] on in-hospital mortality, physical disability, and the need for rehabilitation transfer. RESULTS: A higher NIHSS score was a critical risk factor for each outcome and the only significant factor for in-hospital mortality [odds ratio (OR)/point 1.156, 95% confidence interval (CI) 1.054-1.267]. The risk factors of physical disability were NIHSS score (OR/point 1.458, 95% CI 1.064-1.998), older age (OR/year 1.141, 95% CI 1.022-1.274), diabetic nephropathy (OR 7.096, 95% CI 1.066-47.218), and higher premorbid modified Rankin scale (mRS) score (OR/grade 2.144, 95% CI 1.155-3.978); while those of rehabilitation transfer were a higher NIHSS score (OR/point 1.253, 95% CI 1.080-1.455), dialysis vintage (OR/year 1.175, 95% CI 1.024-1.349), and intradialytic hypotension before onset (OR 5.430, 95% CI 1.320-22.338). CONCLUSIONS: Along with neurological severity, dialysis vintage, intradialytic hypotension, and diabetic nephropathy could worsen the prognosis of patients with AIS undergoing hemodialysis.

Kidney function, blood pressure and proteinuria were associated with pregnancy outcomes of pregnant women with chronic kidney disease: a single-center, retrospective study in the Asian population.

BACKGROUND: Studies among pregnant Asian women with chronic kidney disease (CKD) have not been widely performed; therefore, clinical criteria for these patients have not been well established. METHODS: We conducted a retrospective study among pregnant women with CKD who received prenatal care at our institution for 8 consecutive years. Primary outcome was the development of severe adverse events (SAEs). We analyzed correlations between primary outcome and CKD parameters [age, body mass index (BMI), estimated glomerular filtration rate (eGFR), urinary protein-creatinine ratio (UP), systolic blood pressure (SBP), diastolic blood pressure (DBP), and not normal blood pressure (non-NBP)] at the time of referral. Secondary outcomes were low birth weight (LBW), preterm delivery (PreD), and small for gestational age (SGA). We divided into two categories, CKD stage G1, and G2 or higher according to eGFR, and proteinuria negative and proteinuria positive according to UP, respectively. RESULTS: We observed 89 pregnancies. SAE was observed in 28 pregnancies. In live birth cases, there were 28 PreD, 28 LBW and 13 SGA. Major SAEs included preeclampsia, superimposed preeclampsia, unscheduled cesarean section, neonatal intensive care unit admission, and fetal death. Stepwise logistic regression analysis selected eGFR (OR = 0.847, p = 0.026), SBP (OR = 1.897, p = 0.006) and proteinuria positive (OR = 2.96, p = 0.046) as the significant predictors of SAEs. There were no significant differences among the baseline characteristics stratified by SGA. CONCLUSIONS: This is the first study to report pregnancy outcomes among Japanese non-disease-oriented patients with CKD. In Asians, especially in the Japanese population, kidney function, blood pressure and proteinuria might affect pregnancy outcomes.

Questionnaire survey on the prescription of renal replacement therapy for acute phase patients on maintenance dialysis who developed cerebrovascular disease.

BACKGROUND: There is limited information about acute phase renal replacement therapy (RRT) for maintenance hemodialysis patients after the onset of cerebrovascular disease. This study aimed to investigate which modality of renal replacement therapy is currently selected in practice. METHODS: We conducted a mail-based survey in 317 dialysis facilities that were certified by three academic societies that focus on dialysis, neurology, and neurosurgery in Japan. RESULTS: We received responses from 103 facilities (32.5%). In cases of cerebral infarction (CI) and intracerebral hemorrhage (ICH), more than 80% of the facilities selected only intermittent RRT, and 22.3% (CI)/8.7% (ICH) of the facilities selected intermittent HD which is the same setting in normal conditions. Although continuous hemodiafiltration and peritoneal dialysis are recommended in the Japanese guidelines, these were selected in only a few facilities: 16.5% and 0% in CI, 16.5% and 1% in ICH, respectively. RRT on the day of onset tended to be avoided, irrespective of the duration following the last HD session. Furthermore, physicians preferred to modify anticoagulants and reduce dialysis performance in the acute phase. CONCLUSION: This questionnaire survey uncovered a gap between guidelines and actual practice, even in hospitals accredited as educational facility, which is a novel and important finding. Further studies with larger sample sizes are needed to determine the optimal modality of RRT for the acute phase of cerebrovascular disease.

Impact of lower body mass index on risk of all-cause mortality and infection-related death in Japanese chronic kidney disease patients.

BACKGROUND: Several studies have reported that lower body mass index (BMI) is associated with high mortality in patients with chronic kidney disease (CKD). Rate of infection-related death in CKD patients is increasing. However, the relationship between BMI and infection-related death is unclear. METHODS: Overall, 2648 CKD outpatients (estimated glomerular filtration rate < 60 mL/min and/or presenting with proteinuria) under the care of nephrologists were prospectively followed for 5 years. Patients were stratified by quartile of BMI levels. Data on all-cause mortality before progression to end-stage kidney disease (ESKD) and the cause of death were collected. RESULTS: The median follow-up time was 3.9 years (interquartile range, 1.7-5.0); 114 patients died and 308 started renal replacement therapy. The leading causes of death were as follows; cardiovascular (41%), infection-related (21%), and malignancy-related (18%). Advanced age and lower BMI were the significant risk factors for all-cause mortality before progression to ESKD. Advanced age was statistically associated with respective causes of death, while lower BMI was associated with infection-related death only. CKD stage had no significant impact on all-cause or individual mortality. CONCLUSIONS: Low BMI was associated with significant risk of all-cause mortality and infection-related death, which may indicate the novel clinical target to improve CKD outcomes.

Diabetes mellitus as a cause or comorbidity of chronic kidney disease and its outcomes: the Gonryo study.

BACKGROUND: Diabetes mellitus (DM) is a major cause of end-stage kidney disease (ESKD). However, the difference in renal outcomes between DM patients with non-diabetic renal disease (DM and NDRD) and those with diabetic nephropathy (DN) is controversial. The aim of the present study was to evaluate the differences among patients with DN, DM, and NDRD, and non-DM chronic kidney disease (CKD) in a prospective observational study. METHODS: We extracted the data of 2484 patients from 11 nephrology care centers and categorized into three groups as described above. The primary outcome was ESKD requiring renal replacement therapy. RESULTS: During the median follow-up of 4.44 years, 281 patients (11.3%) developed ESKD. Renal outcomes of DM and NDRD patients were similar to those of non-DM patients (p ≥ 0.05). At CKD stage G3b, the hazard ratios (95% confidence intervals) of ESKD were 7.10 (2.46-20.49) in DN patients and 0.89 (0.19-4.24) in DM and NDRD. The annual change in the estimated glomerular filtration rate (eGFR) in DN patients was significantly larger than that in other groups at stage G3b (-9.7%/year). CONCLUSIONS: We found that DN patients have a higher risk for ESKD than DM and NDRD or non-DM patients. In particular, GFR rapidly declined in DN at stage G3b. DM and NDRD patients can accomplish equally beneficial renal outcomes as non-DM CKD, regardless of their similar metabolic profiles as DN. In conclusion, we should prudentially consider the risk stratification of DM whether cause or comorbidity of CKD.

Impact of hemoglobin levels on renal and non-renal clinical outcomes differs by chronic kidney disease stages: the Gonryo study.

BACKGROUND: Anemia greatly affects the development of renal and cardiovascular outcomes in chronic kidney disease (CKD) patients. However, the impact based on CKD stage remains unclear. METHODS: We prospectively followed 2,602 Japanese CKD patients under the care of nephrologists. CKD was defined according to cause, estimated glomerular filtration rate <60 mL/min, and/or proteinuria. Patient outcomes [primary end-points: cardiovascular events (CVEs), all-cause mortality, and end-stage kidney disease (ESKD) requiring renal replacement therapy] were assessed in association with basal hemoglobin (Hb) levels (<10, 10-12 and ≥12 g/dL), stratified by CKD stages. RESULTS: During follow-up, 123 patients developed CVEs, 41 died, and 220 progressed to ESKD. For stages G3, G4 and G5, ESKD frequencies were 2.8, 64.4, and 544.8 person-years, while CVEs and death were 25.6, 45.6, and 76.3 person-years, respectively. The combined endpoint rate was significantly higher in patients with Hb <10 versus Hb 10-12 g/dL, but a higher risk for CVEs and death with Hb <10 g/dL was found only in G3 [hazard ratio (HR) 4.49, (95 % confidence interval (95 % CI) 2.06-9.80)]. In contrast, risk for ESKD with Hb <10 g/dL was found only in G4 [HR 3.08 (95 % CI 1.40-6.79)] and G5 [HR 1.43 (95 % CI 1.01-2.05)]. No increased risks with higher Hb levels were found. CONCLUSION: The impact of renal anemia of Hb <10 g/dL on clinical outcomes differed by CKD stage, with a significantly high risk for CVEs and all-cause mortality in G3 and progression to ESKD in G4 and G5.

Relationship between low blood pressure and renal/cardiovascular outcomes in Japanese patients with chronic kidney disease under nephrologist care: the Gonryo study.

BACKGROUND: Previous studies established a J-shaped association between blood pressure (BP) and cardiovascular disease (CVD) in chronic kidney disease (CKD), and the different clinical profiles of CVD by ethnicity. However, the adequately lower BP target remains unclear in Asian patients with CKD. METHODS: This prospective observational study included 2,655 Japanese outpatients with CKD under nephrologist care who met the inclusion criteria, namely estimated glomerular filtration rate <60 mL/min and/or presenting proteinuria. The patients were divided by 10-mmHg BP increments by clinical data. The end points were death, cardiovascular events (CVEs), and end-stage kidney disease (ESKD) that requires renal replacement therapy. RESULTS: During a 3.02-year median follow-up, 64 patients died, 120 developed CVEs, and 225 progressed to ESKD. In the adjusted Cox models, the risks of CVEs and all-cause mortality were higher in the patients with systolic BPs (SBPs) < 110 mmHg than in those with SBPs of 130-139 mmHg. Moreover, the risk was higher in those with diastolic BPs (DBPs) < 70 mmHg than in those with DBPs of 80-89 mmHg. Although SBPs ≥ 140 mmHg were associated with higher incidence rates of ESKD, no significant increased risk was associated with BPs < 130/80 mmHg. CONCLUSIONS: SBPs < 110 mmHg and DBPs < 70 mmHg were independent risk factors of CVEs and all-cause mortality. No lower BPs were observed as significant risk factors of progression to ESKD. This study suggests that the lower BP target in Asian patients with CKD should be ≥110/70 mmHg.

Tubulointerstitial Nephritis after Using a Sodium-glucose Cotransporter 2 Inhibitor.

We herein report a case of acute kidney injury (AKI) due to tubulointerstitial nephritis (TIN) after starting empagliflozin in a diabetic patient. The patient developed stage 1 AKI with proteinuria and elevated tubulointerstitial markers. A renal biopsy showed acute TIN with lymphocytic infiltration into the interstitium. The patient's renal function improved after discontinuation of empagliflozin and steroid administration. Sodium-glucose cotransporter 2 (SGLT2) inhibitor-induced AKI has been reported, but the underlying mechanism remains unclear, potentially because few patients with SGLT2-inhibitor-induced AKI have undergone a renal biopsy. We report the present case in the hope that it will help clarify the mechanism.

Methylglyoxal Induces Inflammation, Metabolic Modulation and Oxidative Stress in Myoblast Cells.

Uremic sarcopenia is a serious clinical problem associated with physical disability and increased morbidity and mortality. Methylglyoxal (MG) is a highly reactive, dicarbonyl uremic toxin that accumulates in the circulatory system in patients with chronic kidney disease (CKD) and is related to the pathology of uremic sarcopenia. The pathophysiology of uremic sarcopenia is multifactorial; however, the details remain unknown. We investigated the mechanisms of MG-induced muscle atrophy using mouse myoblast C2C12 cells, focusing on intracellular metabolism and mitochondrial injury. We found that one of the causative pathological mechanisms of uremic sarcopenia is metabolic flow change to fatty acid synthesis with MG-induced ATP shortage in myoblasts. Evaluation of cell viability revealed that MG showed toxic effects only in myoblast cells, but not in myotube cells. Expression of mRNA or protein analysis revealed that MG induces muscle atrophy, inflammation, fibrosis, and oxidative stress in myoblast cells. Target metabolomics revealed that MG induces metabolic alterations, such as a reduction in tricarboxylic acid cycle metabolites. In addition, MG induces mitochondrial morphological abnormalities in myoblasts. These changes resulted in the reduction of ATP derived from the mitochondria of myoblast cells. Our results indicate that MG is a pathogenic factor in sarcopenia in CKD.

Postprandial metabolic response to a fat- and carbohydrate-rich meal in patients with chronic kidney disease.

BACKGROUND: While chronic kidney disease (CKD) is associated with dysmetabolism including a marked insulin resistance, the postprandial response has not comprehensively been studied in CKD patients. METHODS: We conducted an intervention study comparing fasting and postprandial circulating biomarkers of glucose and lipid homeostasis, incretins, anabolic hormones, inflammation and oxidative stress in nine prevalent non-diabetic hemodialysis (HD) patients and 10 matched controls assessed after a standardized meal consisting of 75 g of milk fat, 80 g of carbohydrates and 6 g of proteins/m(2) of body surface area. RESULTS: Glucose and triglyceride increased in a similar manner following the meal, while insulin, C-peptide and glucose-dependent insulinotropic polypeptide increased more in HD patients. HDL and LDL cholesterol decreased slightly with no significant difference between the groups. The elevated baseline growth hormone (GH) in patients dropped, resulting in comparable levels in both groups 240 min after the meal; however, there was no change in insulin-like growth factor 1 (IGF-1) levels. No marked changes of interleukin 6 and tumor necrosis factor-α were observed in either group. An elevation in the DNA oxidative product 8-hydroxydeoxyguanosine was observed in HD patients. CONCLUSIONS: The postprandial state in CKD is characterized by impaired insulin sensitivity with increased incretin levels, along with GH/IGF-1 axis uncoupling and an elevation in an oxidative stress marker.

Different clinical impact of hyperuricemia according to etiologies of chronic kidney disease: Gonryo Study.

BACKGROUND: Hyperuricemia is highly prevalent in chronic kidney disease (CKD) patients, but the evidence for a relationship between uric acid (UA) and clinical outcomes in CKD patients is limited and inconsistent. We hypothesized that UA has a different impact on clinical outcomes according to the underlying disease causing CKD. METHODS: This study prospectively investigated the associations between UA and renal and non-renal outcomes according to the underlying disease causing CKD in 2,797 Japanese patients under the care of nephrologists. The patients were categorized into four groups: primary renal disease (n = 1306), hypertensive nephropathy (n = 467), diabetic nephropathy (n = 275), and other nephropathy (n = 749). The renal outcome was defined as end-stage renal disease (ESRD), and the non-renal outcome was defined as a composite endpoint of cardiovascular events (CVEs) and all-cause mortality. RESULTS: During a median 4.8-year follow-up, 359 (12.8%) patients reached the renal outcome, and 260 (9.3%) reached the non-renal outcome. In the all-patient analysis, hyperuricemia was not associated with the risks for renal and non-renal outcomes, but in primary renal disease (PRD) and hypertensive renal disease (HTN) patients, hyperuricemia was significantly associated with non-renal outcomes. Per 1 mg/dl higher UA level, multivariable adjusted hazard ratio was 1.248 (95% CI: 1.003 to 1.553) for PRD, and 1.250 (1.035 to 1.510) for HTN. Allopurinol did not reduce the risks for renal and non-renal outcomes, both in all patients and in the subgroup analysis. CONCLUSIONS: The effect of hyperuricemia on clinical outcomes in CKD patients varies according to the underlying disease causing CKD. Hyperuricemia is an independent risk factor for non-renal outcomes in primary renal disease and hypertensive renal disease patients. Allopurinol did not decrease the risks for renal and non-renal outcomes.

Renal interstitial fibroblasts coproduce erythropoietin and renin under anaemic conditions.

BACKGROUND: Erythrocyte mass contributes to maintaining systemic oxygen delivery and blood viscosity, with the latter being one of the determinants of blood pressure. However, the physiological response to blood pressure changes under anaemic conditions remain unknown. METHODS AND FINDINGS: We show that anaemia decreases blood pressure in human patients and mouse models. Analyses of pathways related to blood pressure regulation demonstrate that anaemia enhances the expression of the gene encoding the vasopressor substance renin in kidneys. Although kidney juxtaglomerular cells are known to continuously produce renin, renal interstitial fibroblasts are identified in the present study as a novel site of renin induction under anaemic hypotensive conditions in mice and rats. Notably, some renal interstitial fibroblasts are found to simultaneously express renin and the erythroid growth factor erythropoietin in the anaemic mouse kidney. Antihypertensive agents but not hypoxic stimuli induced interstitial renin expression, suggesting that blood pressure reduction triggers interstitial renin induction in anaemic mice. The interstitial renin expression was also detected in injured fibrotic kidneys of the mouse and human, and the renin-expressing interstitial cells in murine fibrotic kidneys were identified as myofibroblasts originating from renal interstitial fibroblasts. Since the elevated expression levels of renin in fibrotic kidneys along with progression of renal fibrosis were well correlated to the systemic blood pressure increase, the renal interstitial renin production seemed to affect systemic blood pressure. INTERPRETATION: Renal interstitial fibroblasts function as central controllers of systemic oxygen delivery by producing both renin and erythropoietin. FUNDING: Grants-in-Aid from Japan Society for the Promotion of Science (JSPS) KAKENHI (17K19680, 15H04691, and 26111002) and the Takeda Science Foundation.

Clinical importance of an elevated circulating chemerin level in incident dialysis patients.

BACKGROUND: Circulating chemerin, a novel adipokine linked to obesity, glucose tolerance and hyperlipidaemia, was recently reported to be increased in chronic kidney disease (CKD) patients. We explored possible links between chemerin and various clinical, nutritional and biochemical markers as well as its association with 5-year all-cause mortality. METHODS: Fasting plasma samples were obtained from 252 CKD Stage 5 patients [median age 56 years, male 61%, glomerular filtration rate (GFR) 7 mL/min] enrolled at the initiation of dialysis. Serum chemerin was measured using commercial ELISA. Chemerin levels were related to clinical status and biomarkers of inflammation, glucose and lipid metabolism and body composition (body mass index and total and truncal fat mass by dual-energy X-ray absorptiometry). Survival, censored for transplantation, was recorded for a follow-up time of 5 years. RESULTS: In univariate regression, circulating chemerin (119 ± 26 ng/mL) was positively correlated with cholesterol (ρ = 0.21; P = 0.001), triglycerides (ρ = 0.22; P = 0.0007), apolipoprotein B (ρ = 0.33; P < 0.0001), high-sensitivity C-reactive protein (ρ = 0.18; P = 0.006), white blood cell count (ρ = 0.23; P < 0.001), insulin (ρ = 0.18; P < 0.05) and homeostatic model assessment (HOMA) index (ρ = 0.17; P < 0.05), whereas we found a negative correlation with GFR (ρ = -0.28; P = 0.007), high-density lipoprotein cholesterol (ρ = -0.15; P < 0.05) and homocysteine (ρ = -0.25; P = 0.001). Moreover, a high chemerin predicted a better survival (log-rank χ(2) = 3.85; P < 0.05). Also, in a Cox model, adjustments for age, sex and CRP did not alter this finding (hazard ratio = 1.98 [95% confidence interval = 1.13-3.50], P = 0.01). However, adjusting for GFR made the model non-significant. CONCLUSIONS: We report that, in incident dialysis patients, an elevated chemerin is associated with a survival advantage despite its significant positive association with markers of inflammation and dyslipidaemia.

Enhanced neutrophil apoptosis accompanying myeloperoxidase release during hemodialysis.

Biocompatibility of hemodialysis (HD) systems have been considerably improved. However, mortality and morbidity rates of patients have remained high, raising questions regarding the biocompatibility of current systems. In the present study, 70 patients on regular HD (51 males; mean age, 63 years; median duration of HD, 18 months) with high-performance membrane (polysulfone, 77%; polymethylmethacrylate, 23%) at Tohoku University Hospital were examined. Blood samples before and after HD, were subjected to measure apoptosis cells of white blood cells, plasma levels of the following molecules: myeloperoxidase (MPO), pentraxin 3 (PTX3), angiogenin, complements, and 17 cytokines. The main findings were as follows: significant decreases in leukocyte counts by dialysis, significant increases in apoptosis-positive leukocytes by dialysis (neutrophils and monocytes), and significant decrease in plasma angiogenin accompanying increase in plasma MPO and PTX3 levels, with no or only marginal changes in plasma pro-inflammatory cytokine levels and complement products by dialysis. The findings underlined the unsolved issue of bio-incompatibility of HD systems, and suggest the possible pathology of neutrophil apoptosis accompanying MPO release for the development of microinflammation in patients on HD.

Leptin and uremic protein-energy wasting--the axis of eating.

Leptin, a regulator of eating behavior, is secreted by adipocytes and affects energy homeostasis in health and disease. Specifically, leptin is implicated in modulating multiple pathways controlling energy intake, energy expenditure and the allocation of precious nutrients between conversion, storage, and consumption. Whereas leptin has been shown to be a major determinant of anorexia in uremic animals, human data are so far unclear. Regardless, multiple studies have demonstrated that patients with chronic kidney function impairment have elevated leptin levels, although these levels still correlate strongly with body fat mass. In the present publication, we will review the current evidence for the pathophysiological role of leptin, focusing on chronic kidney disease (CKD) patients.

Functional polymorphisms in the transcription factor NRF2 in humans increase the risk of acute lung injury.

We recently used positional cloning to identify the transcription factor Nrf2 (NF-E2 related factor 2) as a susceptibility gene in a murine model of oxidant-induced acute lung injury (ALI). NRF2 binds to antioxidant response elements (ARE) and up-regulates protective detoxifying enzymes in response to oxidative stress. This led us to investigate NRF2 as a candidate susceptibility gene for risk of development of ALI in humans. We identified multiple single nucleotide polymorphisms (SNPs) by resequencing NRF2 in ethnically diverse subjects, and one (-617 C/A) significantly (P<0.001) diminished luciferase activity of promoter constructs containing the SNP and significantly decreased the binding affinity (P<0.001) relative to the wild type at this locus (-617 CC). In a nested case-control study, patients with the -617 A SNP had a significantly higher risk for developing ALI after major trauma (OR 6.44; 95% CI 1.34, 30.8; P=0.021) relative to patients with the wild type (-617 CC). This translational investigation provides novel insight into the molecular mechanisms of susceptibility to ALI and may help to identify patients who are predisposed to develop ALI under at risk conditions, such as trauma and sepsis. Furthermore, these findings may have important implications in other oxidative stress related illnesses.

(Pro)renin receptor is involved in mesangial fibrosis and matrix expansion.

(Pro)renin receptor [(P)RR] is expressed in the kidney and is involved in renal injury. Although (P)RR is activated by indoxyl sulfate (IS) and may be related to renal injury, the details remain unclear. We used mouse mesangial cell line SV40 MES13 to investigate the association of (P)RR with mesangial fibrosis or expansion. Furthermore, we examined the correlation between serum soluble (P)RR [s(P)RR] and various laboratory data including serum IS, a uremic toxin that induces renal fibrosis through (P)RR, and pathological indices in chronic kidney disease and particularly in IgA nephropathy patients. In vitro study using SV40 MES13 cells revealed that (P)RR expression significantly increased in the presence of IS. IS stimulated the fibrotic factors' expression, which was significantly suppressed by (P)RR knockdown. Moreover, it significantly increased the expression of matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 via the ERK1/2 pathway. In addition, the s(P)RR level significantly correlated with serum IS and mesangial injury markers in our patients. Our results suggest that (P)RR is associated with mesangial fibrosis and matrix expansion through the IS-(P)RR-ERK1/2 pathway. Clinically, s(P)RR may be a biomarker of mesangial fibrosis and matrix expansion.