Ferric Citrate Decreases Fibroblast Growth Factor 23 and Improves Erythropoietin Responsiveness in Hemodialysis Patients.

BACKGROUND: Serum phosphate and vitamin D receptor activator regulate fibroblast growth factor 23 (FGF23), and iron may modulate FGF23 metabolism. The aim of the present study was to elucidate the effects of ferric citrate hydrate and lanthanum carbohydrate on serum FGF23 levels in hemodialysis patients. METHODS: This prospective, open-label, multicenter study enrolled 60 patients on hemodialysis treated with lanthanum carbonate. Patients were randomly assigned to 2 groups: those switching from lanthanum carbonate to ferric citrate hydrate (ferric citrate group, n = 30) or those continuing lanthanum carbonate (control group, n = 30). Patients were monitored for 24 weeks. Endpoints included changes in FGF23, phosphate, and the dose of erythropoiesis stimulating agent (ESA), erythropoietin responsiveness index (ERI), and adverse events. RESULTS: FGF-23 levels were significantly lower in the ferric citrate group compared with the levels in the control group (change from baseline -6,160 vs. -1,118 pg/mL; p = 0.026). There were no significant changes in serum calcium, phosphate, and intact parathyroid hormone levels in either group. The ferric citrate group had significantly increased serum iron, ferritin, and transferrin saturation. Hemoglobin levels were significantly elevated, and the dose of ESA was significantly decreased in the ferric citrate group but not in the control group. ERI and the dose of intravenous saccharated ferric oxide were significantly lower in the ferric citrate group compared with those of the control group (p = 0.015 and p = 0.002). CONCLUSION: In patients on hemodialysis, 24-week treatment with ferric citrate hydrate resulted in significant reduction in FGF23 and ERI independently of serum phosphate level.

Glycated Albumin versus Glycated Hemoglobin as a Glycemic Indicator in Diabetic Patients on Peritoneal Dialysis.

Compared with glycated hemoglobin (HbA1c), glycated albumin (GA) is superior in estimating glycemic control in diabetic patients on hemodialysis (HD). However, the better index for assessment of glycemic control in diabetic patients on peritoneal dialysis (PD) and the impact of protein loss on GA are unknown. Twenty diabetic patients on HD were matched by age, sex, and baseline postprandial plasma glucose (PG) levels to 20 PD patients. PG, HbA1c, GA, and serum albumin levels were measured for six months. Protein loss in PD patients was estimated by measuring the protein concentration in the peritoneal dialysate and by 24 h urine collection. Although PG and HbA1c did not differ significantly between the groups, the PD group had significantly lower GA (17.8% versus 20.8%, p < 0.001) and GA/HbA1c ratio (2.95% versus 3.45%, p < 0.0001) than the HD group. Although the PG level correlated significantly with the GA levels in both groups, it was not correlated with the HbA1c levels in both groups. HbA1c level was negatively associated with erythropoiesis-stimulating agent (ESA) dose in both groups, whereas GA was not significantly associated with serum albumin, hemoglobin concentration, ESA dose, and protein loss. Multiple regression analysis identified GA as the only independent factor associated with PG in PD patients. Our results suggested that GA was not significantly associated with protein loss, hemoglobin, serum albumin, and ESA dose. Although GA might underestimate glycemic status, it provided a significantly better measure for estimating glycemic control than HbA1c, even in PD patients.

Urinary ACE2 is associated with urinary L-FABP and albuminuria in patients with chronic kidney disease.

AIM: Angiotensin-converting enzyme 2 (ACE2) is expressed in the kidney and may be a renoprotective enzyme since it converts angiotensin (Ang) II to Ang-(1-7). In addition, ACE2 has been detected in urine from patients with chronic kidney disease (CKD). The aim of this study was to determine the urinary ACE2 levels in patients with various stages of CKD and to identify the factors associated with the presence of ACE2. METHODS: We assessed 152 patients with CKD stage G1-G4. The patients were classified according to the presence or absence of diabetes mellitus (DM) (DM group, n = 72; non-DM group, n = 80) and according to the estimated glomerular filtration rate (CKD stage G1/2 group, n = 40; CKD stage G3 group, n = 74; and CKD stage G4 group, n = 38). Parameters were urinary ACE2, urinary albumin/ creatinine ratio (UACR), urinary liver-type fatty acid binding protein (L-FABP), estimated glomerular filtration rate, and other factors determined to be associated with elevated urinary ACE2. RESULTS: Urinary ACE2 was significantly higher in patients with diabetes (p = 0.01) and in patients with CKD stage G4 compared with stages G1-G3 (p < 0.0001). Multivariable regression analysis revealed that urinary L-FABP and UACR were significantly associated with urinary ACE2 levels, indicating that urinary ACE2 is increased in patients with diabetes and advanced stage CKD. CONCLUSION: ACE2 might continuously protect from both glomerular and tubulointerstitial injury during CKD progression. Taken together, urinary ACE2 might be a marker of kidney renin-angiotensin system activation in such patients.

Randomized Controlled Trial of Darbepoetin α Versus Continuous Erythropoietin Receptor Activator Injected Subcutaneously Once Every Four Weeks in Patients with Chronic Kidney Disease at the Pre-Dialysis Stage.

Continuous erythropoietin receptor activator (CERA) seems to maintain a stable hemoglobin (Hb) level because its half-life is longer than darbepoetin α (DA). Twenty chronic kidney disease (CKD) patients at the pre-dialysis stage who had been administered DA for over 24 weeks were randomly assigned to receive subcutaneous CERA or DA once every four weeks during 48 weeks. In both groups, the rate of achievement of target Hb level changed from 70% to 100% in weeks 0 to 48, with no significant difference between the groups. Compared with week 0, the Hb level was significantly increased from week 24 in the DA group and from week 8 in the CERA group. In addition, the reticulocyte count was significantly increased from week 4 in the CERA group compared with the DA group. There was no significant difference in the levels of estimated glomerular filtration rate and iron status between both groups. Because of the small number of patients in this study, only limited conclusions can be drawn. However, the results suggest that subcutaneous administration of DA or CERA once every four weeks to predialysis patients has similar effects on achievement of target Hb levels.

L/N-type calcium channel blocker cilnidipine reduces plasma aldosterone, albuminuria, and urinary liver-type fatty acid binding protein in patients with chronic kidney disease.

Cilnidipine inhibits both L- and N-type calcium channels and has been shown to dilate efferent arterioles as effectively as afferent arterioles. We conducted an open-label, randomized trial to compare the effects of cilnidipine against those of amlodipine on blood pressure (BP), albuminuria, and plasma aldosterone concentration in hypertensive patients with mild- to moderate-stage chronic kidney disease. Patients with BP ≥130/80 mmHg, an estimated glomerular filtration rate of 90-30 ml/min/1.73 m(2), and albuminuria ≥30 mg/g, despite treatment with the maximum recommended dose of angiotensin II receptor blockers, were randomly assigned to two groups. Patients received either 10 mg/day cilnidipine (increased to 20 mg/day; n = 35) or 2.5 mg/day amlodipine (increased to 5 mg/day; n = 35). After 48 weeks of treatment, a significant and comparable reduction in systolic and diastolic BP was observed in both groups. The percent reduction in the urinary albumin to creatinine ratio and liver-type fatty acid binding protein (L-FABP) in the cilnidipine group was significantly greater than in the amlodipine group. Although plasma renin activity did not differ between the two groups, the plasma aldosterone level was significantly decreased in the cilnidipine group. Cilnidipine therefore appears to reduce albuminuria, urinary L-FABP, and plasma aldosterone levels more than amlodipine, and these effects are independent of BP reduction.

Efficacy analysis of the renoprotective effects of aliskiren in hypertensive patients with chronic kidney disease.

We aimed to assess the effect of aliskiren treatment on blood pressure, albuminuria, and kidney function in patients with chronic kidney disease (CKD). We conducted a prospective, open-label study of 67 patients with CKD who were already being treated with other antihypertensives. Inclusion criteria were blood pressure (BP) ≥130/80 mmHg, albuminuria ≥30 mg/g, and estimated glomerular filtration rate (eGFR) >30 ml/min/1.73 m(2). Subjects were treated with 150 mg/day aliskiren, which was increased to 300 mg/day for the 24-week study period. Aliskiren effectively reduced both systolic and diastolic BP, plasma renin activity (PRA), serum aldosterone concentration, albuminuria, urinary N-acetyl-glucosaminidase, and urinary ß2-microglobulin levels. Although eGFR was significantly decreased after 4 weeks of aliskiren treatment, it recovered to a pretreatment level within 12 weeks of treatment initiation. There were no significant differences in the percent reduction of albuminuria or changes of eGFR levels when the subjects were divided into three groups on the basis of baseline eGFR (stages 1/2, 3, and 4) and the presence or absence of diabetes mellitus (DM group and non-DM group). Furthermore, in patients not treated with renin-angiotensin-aldosterone-system (RAAS) inhibitors, including angiotensin receptor blockers or angiotensin-converting enzyme inhibitors at baseline, changes in eGFR were significantly increased compared with those already treated with RAAS inhibitors at baseline. Aliskiren administration reduced BP, PRA, serum aldosterone levels, and albuminuria, while maintaining eGFR, regardless of the presence or absence of DM or the degree of eGFR.

Aliskiren reduces home blood pressure and albuminuria in patients with hypertensive nephrosclerosis.

BACKGROUND: The aim of this study was to investigate the antialbuminuric and antihypertensive effects of aliskiren by monitoring home blood pressure (BP) in comparison with the effects of the angiotensin receptor blocker (ARB) valsartan in patients with hypertensive nephrosclerosis and albuminuria. METHODS: We conducted an open-label, randomized trial to compare the effects of aliskiren with those of valsartan. Patients with BP <150/90 mmHg, an estimated glomerular filtration rate of 90-30 mL/min/1.73 m(2), and albuminuria >30 mg/g, despite treatment with a 160 mg daily dose of valsartan, were randomly assigned to the following two groups: the aliskiren group, who switched from 160 mg/day valsartan to 150 mg/day aliskiren, which was later increased to 300 mg/day (n = 20); and the valsartan group, who continued with 160 mg/day valsartan (n = 20). RESULTS: After 12 weeks of treatment, although there was no significant difference in clinic BP between groups, a significant reduction in morning and evening systolic BP was observed in the aliskiren group. The decrease in albuminuria in the aliskiren group was significantly better than that in the valsartan group, and a significant correlation was noted between the change in morning systolic BP and the change in albuminuria in the aliskiren group (r = 0.564, P = 0.0084). CONCLUSION: We showed that aliskiren treatment leads to a greater reduction in albuminuria and home systolic BP values than valsartan in patients with nephrosclerosis. We propose that aliskiren therapy should be considered as a therapeutic modality to complement ARBs in hypertensive patients with nephrosclerosis.

Changes to prothrombin international normalized ratio in patients receiving hemodialysis.

BACKGROUND: The clinical utility of factor Xa inhibitors (xabans) has been demonstrated, but these inhibitors are contraindicated in patients undergoing dialysis therapy. Therefore, warfarin remains the mainstay for oral anticoagulation treatment of patients receiving hemodialysis (HD). OBJECTIVE: This study investigated the changes in international normalized ratio (INR) during HD treatment of patients receiving warfarin. METHODS: Changes in INR and serum albumin levels were determined before (pre-) and after (post-) HD in six consecutive HD sessions. 30 patients (23 males, 7 females; mean age, 72 ± 8 years) were enrolled, and a total of 180 measurements were performed. RESULTS: Post-HD INR levels were significantly decreased compared with pre-HD levels (2.07 ± 0.52 to 1.99 ± 0.50, p < 0.0001), while serum albumin levels were significantly increased post-HD compared with pre-HD (p < 0.0001). There was a significant negative correlation between changes in INR and serum albumin during HD (r = -0.383, p = 0.0002). CONCLUSION: INR is significantly decreased post-HD compared with pre-HD. Although the therapeutic range of INR differs according to the disease, close monitoring of the degree of anticoagulation in patients receiving warfarin is recommended to minimize the risk of thrombosis and hemorrhagic complications.

International normalized ratio decreases after hemodialysis treatment in patients treated with warfarin.

This study determined the changes in international normalized ratio (INR) that occur during hemodialysis (HD) treatment of patients receiving warfarin. Twenty patients were enrolled in the study (15 males, 5 females; mean age, 71 ± 7 years). We investigated changes in INR and R-isomer and S-isomer of warfarin concentrations before (pre-) and after (post-) HD. Post-HD INR levels were significantly decreased compared with pre-HD levels (P < 0.01), whereas plasma concentrations of both R-isomer and S-isomer of warfarin were significantly increased post-HD compared with pre-HD (P < 0.01). There was a negative correlation between INR changes and changes in warfarin concentration or changes in serum albumin levels during HD. Multivariate analysis revealed that change of serum albumin was the only factor that was significantly related to the change of INR (P = 0.0051, R = 0.501). We suggest that the free fraction of plasma warfarin decreased with increases in serum albumin levels because the protein-binding rate of warfarin is very high and free fractions were bound to albumin during HD sessions. The INR depletion was therefore dependent on circulating plasma volumes and serum albumin concentrations. Caution should be taken for those HD patients who have absolute indications of anticoagulation therapy with warfarin.

A case of femoral hemorrhage in a patient with microscopic polyangiitis with low levels of myeloperoxidase-antineutrophil cytoplasmic autoantibody.

We present the case of a 67-year-old female with femoral hemorrhage accompanied by microscopic polyangiitis. She was admitted to our hospital with symptoms of general fatigue, fever, and edema of the lower limbs. She was diagnosed with microscopic polyangiitis on the basis of the cardinal symptoms of the condition, including rapidly progressive glomerulonephritis and the presence of myeloperoxidase-antineutrophil cytoplasmic autoantibody (MPO-ANCA), albeit at a low titer. Renal biopsy demonstrated the presence of fibrocellular crescent-shaped glomeruli with interstitial infiltration. No immune deposits were detected in immunofluorescence studies. The patient was treated with steroids and anti-platelet agents; subsequently, the inflammatory reaction subsided and MPO-ANCA and C-reactive protein titers decreased. However, on day 14, the patient experienced sudden onset of swelling in the left femoral region accompanied by hypotension. Her hemoglobin level dropped from 8.8 to 4.5 g/dl in the subsequent hours. Although computed tomography of the legs revealed an extensive hematoma in the left quadriceps femoris muscle, the patient recovered after receiving a transfusion and supportive therapy with discontinuation of dipyridamole. Thereafter, her renal function improved, and she was discharged. To our knowledge, this is the first report of a case of microscopic polyangiitis accompanied by femoral hemorrhage.

Efficacy analysis of the lipid-lowering and renoprotective effects of rosuvastatin in patients with chronic kidney disease.

We aimed to assess the effects of rosuvastatin treatment on lipid levels, albuminuria, and kidney function in patients with chronic kidney disease (CKD). We conducted a prospective, open-label, study of 91 patients with CKD, low-density lipoprotein cholesterol (LDL-C) levels > 120 mg/dL, and well-controlled blood pressure who were undergoing treatment with renin-angiotensin system inhibitors. Subjects were treated with 2.5 mg/day rosuvastatin, which was increased to 10 mg/day for the 24-week study period. Rosuvastatin effectively reduced total cholesterol, LDL-C, triglycerides, non-high density lipoprotein cholesterol (non-HDL-C) levels, and the LDL-C/HDL-C ratio. Although there was no significant change in the estimated glomerular filtration rate (eGFR), serum cystatin C levels and urinary albumin/creatinine ratio were significantly decreased. Subjects were divided into 2 groups: with and without diabetes mellitus (DM). Percent changes of HDL-C, C-reactive protein (CRP), and malondialdehyde-modified (MDA)-LDL were significantly higher in the DM group than in the non-DM group. Furthermore, when the subjects were divided into 2 groups based on eGFR levels (60 mL/min/1.73 m(2) or more, normal-GFR group; less than 60 mL/min/1.73 m(2), decreased-GFR group), the percent reduction of non-HDL-C, CRP, MDA-LDL levels, and albuminuria of DM subjects in the decreased-GFR group were significantly higher than those in the non-DM subjects. Multivariate analysis identified a change in cystatin C to be associated with decreased albuminuria during rosuvastatin treatment. Rosuvastatin administration reduced albuminuria, serum cystatin C levels, and inflammation, and improved lipid profiles, regardless of the presence or absence of DM, and the degree of the eGFR.

The dipeptidyl peptidase-4 (DPP-4) inhibitor vildagliptin improves glycemic control in type 2 diabetic patients undergoing hemodialysis.

The potent and selective dipeptidyl peptidase-4 inhibitor vildagliptin improves glycemic control in patients with type 2 diabetes through incretin hormone-mediated increases in both α- and ß-cell responsiveness to glucose. We conducted a prospective, open-label, parallel group, controlled study of 51 patients with type 2 diabetic patients undergoing hemodialysis (HD) during the 24-week study period. Patients were assigned to two groups: the vildagliptin group (n = 30) and the control group (n = 21). Vildagliptin was administered at 50 mg/day for the first 8 weeks. Then doses were titrated by dose-doubling to a maximum of 100 mg/day if hemoglobin A1c (HbA1c) or glycated albumin (GA) target levels had not been reached. No vildagliptin was administered to the controls. The average final dose of vildagliptin was 80 ± 5 mg daily. After 24 weeks, vildagliptin had decreased average HbA1c levels from 6.7 % baseline to 6.1 %, average GA levels from 24.5 % baseline to 20.5 % and average postprandial plasma glucose levels from 186 mg/dL baseline to 140 mg/dL (all p < 0.0001). In the control group, we observed no such changes. Vildagliptin efficacy did not differ according to age or body mass index, but the GA reduction was significantly greater in the anti-diabetic agents-naïve group. Furthermore, in patients with higher baseline GA levels, a higher vildagliptin dosage was required to produce a noticeable effect. No serious adverse effects such as hypoglycemia or liver impairment were observed in any patient. Vildagliptin was effective as a treatment for diabetic patients undergoing HD.

Efficacy and safety of mitiglinide in diabetic patients on maintenance hemodialysis.

Mitiglinide is a rapid- and short-acting insulinotropic sulfonylurea receptor ligand and features rapid hypoglycemic action. To date, no prospective study has evaluated the use of mitiglinide in diabetic patients receiving hemodialysis (HD). In this study we evaluated the efficacy and safety of mitiglinide in diabetic patients on HD. Following an 8-week baseline period, we enrolled a study population of poorly controlled diabetic HD patients who had mean hemoglobin (Hb)A(1c) levels greater than 6.5% at baseline and who were not receiving insulin injection therapy. Patients were administered mitiglinide, 15 mg for those who were younger than 70 years and 7.5 mg for those who were 70 years and older, daily with each meal for the first 8 weeks. Subsequently, the doses were titrated by dose-doubling to a maximum of 30 mg/day if no adverse effects appeared. The efficacy was determined by monitoring glycemic control (plasma glucose, HbA(1c), and glycated albumin levels). Safety and tolerance were determined by monitoring clinical and laboratory parameters during the 24-week study period. The average final dose of mitiglinide was 20.0 +/- 8.6 mg daily. Mitiglinide was effective in reducing not only HbA(1c) and glycated albumin but also fasting plasma glucose levels from baseline from week 4 after the start of treatment. The agent was also effective in reducing triglyceride levels. No serious adverse effects such as hypoglycemia or liver impairment were observed in any patient. However, we could not completely rule out the possibility of a hypoglycemic episode, including silent hypoglycemia due to autonomic neuropathy, and therefore further clinical studies are required. It is necessary to adjust the dose of mitiglinide according to the status of glycemic control or hypoglycemic symptoms of individual patients. Although mitiglinide was effective as a treatment for diabetic patients on HD therapy, it should be initiated at a lower dose in the HD population, compared with the general population of diabetic patients. Mitiglinide can be safely used for diabetic patients on HD, if careful attention is paid to hypoglycemia.

Efficacy of L-carnitine supplementation for improving lean body mass and physical function in patients on hemodialysis: a randomized controlled trial.

BACKGROUND: Carnitine deficiency is common in patients on hemodialysis. However, the efficacy of L-carnitine supplementation for improving lean body mass (LBM) and physical function has not yet been evaluated. METHODS: In this multicenter, prospective, parallel, randomized, controlled trial, 91 patients on hemodialysis who developed carnitine deficiency were randomly assigned to receive injections of 1,000 mg L-carnitine 3 times per week after each hemodialysis session (L-carnitine group) or no injections (control group) with monitoring for 12 months. RESULTS: The data for 84 of the 91 patients were available for analysis (L-carnitine group, n = 42; control group, n = 42). Dry weight and body mass index did not significantly change in the L-carnitine group, but significantly decreased in the control group. Arm muscle area (AMA) did not change significantly in the L-carnitine group but decreased significantly in the control group; the difference in mean AMA between the groups was 6.22% (95% confidence interval [CI] 1.90-10.5; P = 0.037). Hand grip strength did not change significantly in the L-carnitine group, but decreased significantly in the control group. The difference in change in hand grip strength between the groups was 4.27% (95% CI 0.42-8.12; P = 0.030). Furthermore, LBM did not change significantly in the L-carnitine group but decreased significantly in the control group; the difference in mean LBM between the groups was 2.92 % (95% CI 1.28-4.61; P = 0.0007). CONCLUSIONS: L-carnitine supplementation is useful in patients who develop carnitine deficiency on hemodialysis because it maintains physical function and LBM.

Correlation between Aortic Calcification Score and Biochemical Parameters in Hemodialysis Patients.

BACKGROUND: The purpose of this study was to determine the correlation between aortic calcification and demographic and biochemical parameters in hemodialysis patients. SUMMARY: Calcification scores of the aortic arch and abdominal aorta were determined from multi-slice computed tomography scans and evaluated according to the Agatston score. The associations between demographic and biochemical parameters and aortic calcification score were determined. In total, 190 patients were included in the study. There was a significant positive correlation between aortic calcification scores and age, duration of hemodialysis, cardiothoracic ratio, normalized protein catabolic rate, brachial-ankle pulse wave velocity (baPWV), serum markers of mineral metabolism, and inflammation. A significant negative correlation was found between aortic calcification scores and platelet count. Multivariate analysis showed that age, duration of hemodialysis, baPWV, phosphate, calcium and phosphate (Ca×P) product, parathyroid hormone, and C-reactive protein levels were independent risk factors for calcification of the aortic arch, while baPWV and Ca×P product were independent risk factors for calcification of the abdominal aorta. Key Messages: Aortic calcification scores correlate with age, duration of hemodialysis, and several biochemical parameters of inflammation and mineral metabolism.

Targets and Therapeutics for Glycemic Control in Diabetes Patients on Hemodialysis.

BACKGROUND: For diabetes patients without nephropathy, glycemic control is important to reduce the risk or delay the progression of diabetes complications, including nephropathy. In diabetes patients on hemodialysis, good glycemic control is necessary to improve prognosis. Many factors influence the blood glucose level of diabetes patients on hemodialysis, such as factors associated with end-stage kidney disease and factors related to hemodialysis. Therefore, since glucose metabolism in diabetes patients on hemodialysis has unique characteristics, it is necessary to manage blood glucose in these patients with specific guidelines. Here, we describe the targets and therapeutics for glycemic control in diabetes patients on hemodialysis. SUMMARY: According to the guidelines of the Japanese Society for Dialysis Therapy (JSDT) regarding the treatment of diabetes in hemodialysis patients, the target casual plasma glucose level (predialysis blood glucose level) is less than 180-200 mg/dL, the target glycated albumin value is less than 20.0% (less than 24.0% in patients at risk of hypoglycemia). When glycemic control is poor and the plasma glucose level before dialysis is high, hemodialysis-induced hyperglycemia may occur, in which plasma glucose decreases during hemodialysis and appears to rise after hemodialysis. On the other hand, hemodialysis patients with diabetes tend to develop hypoglycemia due to various factors. In addition, autonomic nervous system disorders may complicate the manifestation of hypoglycemia so that these patients may not exhibit symptoms. Thus, particular caution is necessary to prevent hypoglycemia. Key Messages: The plasma glucose level of hemodialysis patients with diabetes may fluctuate under the influence of many factors, such as the state of kidney function, delay in metabolism and excretion of diabetes medicine, and hemodialysis parameters. In particular, patients with poor glycemic control are susceptible to various influences, leading to a wider fluctuation in plasma glucose, with increased risk of both hyperglycemia and hypoglycemia. Since hypoglycemia may lead to a poorer prognosis and quality of life, it is necessary to control plasma glucose levels with the aim of improving the prognosis while avoiding hypoglycemia.

Renoprotective effects of canagliflozin, a sodium glucose cotransporter 2 inhibitor, in type 2 diabetes patients with chronic kidney disease: A randomized open-label prospective trial.

BACKGROUND: To evaluate the renoprotective effects of canagliflozin, we assessed the albuminuria-lowering effect in Japanese type 2 diabetes patients with chronic kidney disease (CKD). METHODS: In this prospective, open-label, parallel-group study, type 2 diabetes patients with CKD were randomized to receive either oral canagliflozin (100 mg/day) or usual care (control group) for 52 weeks. Endpoints included changes in urinary albumin-to-creatinine ratio (UACR), other urinary biomarkers, laboratory parameters, and adverse events. RESULTS: Both groups included 20 patients in the analysis. Mean changes in UACR was -83 (-266 to -31) mg/gCr and 27 (-11 to 131) mg/gCr, in the canagliflozin and control groups, respectively ( p = 0.004). Urinary liver-type free acid binding protein, N-acetyl-ß-d-glucosaminidase, and ß2-microglobulin levels were also significantly decreased in the canagliflozin group, but not in the control group. Mean change in estimated glomerular filtration rate at the end of the study was 0.7 and -3.4 mL/min/1.73 m2 in the canagliflozin and control group, respectively ( p = 0.024). Canagliflozin treatment led to improvement of glycaemic control and reduction in body weight, blood pressure, and liver transaminase. There were no adverse events associated with canagliflozin. CONCLUSION: Canagliflozin was associated with slower progression of kidney disease and reduction in albuminuria and tubulointerstitial markers in diabetes patients with CKD.

Effect of Sucroferric Oxyhydroxide on Fibroblast Growth Factor 23 Levels in Hemodialysis Patients.

OBJECTIVE: This study investigated the effects of sucroferric oxyhydroxide on fibroblast growth factor (FGF)-23 and dose reduction of erythropoiesis-stimulating agents (ESA) and intravenous saccharated ferric oxide in hemodialysis patients. METHODS: In this prospective, open-label, parallel-group, multicenter trial involving patients receiving lanthanum carbonate hydrate, eligible patients were randomized to a sucroferric oxyhydroxide group or a control group. Hemoglobin, serum phosphate, FGF-23, iron, and ferritin levels, as well as transferrin saturation, doses of intravenous saccharated ferric oxide and ESA administered, and the erythropoietin responsiveness index (ERI) were monitored for 24 weeks. RESULTS: Sixty-eight eligible patients were allocated to receive sucroferric oxyhydroxide (n = 34) or serve as controls (n = 34). Data for 31 patients in the sucroferric oxyhydroxide group and 32 in the control group were analyzed. Serum phosphate was equally well controlled in both groups. In the sucroferric oxyhydroxide group, intact FGF-23 levels decreased significantly from baseline at the end of the study (p = 0.01) and there was a significant difference compared with the control group (p = 0.035). Required doses of ESA and ERI were significantly reduced in the sucroferric oxyhydroxide group decreased significantly. The dose of intravenous saccharated ferric oxide required in the sucroferric oxyhydroxide group was significantly lower than that at baseline (p = 0.006) and in the control group (p = 0.003). CONCLUSIONS: Treatment of hyperphosphatemia with sucroferric oxyhydroxide was effective in patients on hemodialysis, resulting in decreased serum FGF-23 levels and a reduction in the required dose of saccharated ferric oxide.

A case report of hemodialysis intolerance with eosinophilia.

We report the case of a patient who developed eosinophilia during hemodialysis and became intolerant to dialysis therapy. The patient, a 40-year-old woman, was initiated on hemodialysis for end-stage renal failure caused by chronic glomerulonephritis. After starting on dialysis, her eosinophil count gradually increased. During the ninth session, she developed abdominal pain of an unknown cause after approximately 1 h of dialysis. The symptom, which persisted in the following sessions, was considered to be a dialysis-related complication. We attempted different dialyzers and anticoagulants, but without improvement. The dialysis therapy was discontinued and steroid treatment was given. The hypereosinophilic condition improved rapidly and dialysis therapy was restarted successfully without causing abdominal pain. To investigate the cause of this problem, we measured the leukocyte count and anaphylatoxin C3a level in peripheral blood during dialysis, and compared the results before and after steroid treatment. The results showed that the significant decrease in the leukocyte count observed before steroid treatment was reduced to a mild decrease after steroid treatment. In contrast, C3a did not show a significant difference between the values obtained before and after steroid treatment. These findings suggest that eosinophilia played an important role in the etiology of dialysis intolerance and that C3a was not involved in the decrease in leukocytes under the conditions experienced by the present patient.

[Development of gene therapy for encapsulating peritoneal sclerosis by a chimeric DNA-RNA hammerhead ribozyme targeting TGF-beta1 mRNA].

BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is a rare and devastating fibrotic complication in patients treated with peritoneal dialysis. Transforming growth factor-beta1 (TGF-beta1) has been reported to be a pivotal factor in the induction of EPS. Ribozymes are RNA molecules that enzymatically cleave the target mRNAs and are expected to be utilized as a novel nucleic acid-based therapy. We examined the effects of the chimeric DNA-RNA hammerhead ribozyme targeting TGF-beta1 mRNA on a peritoneal sclerosis rat model to develop a possible gene therapy for EPS. METHODS: To create an animal model of peritoneal sclerosis, rats were given a daily intraperitoneal injection of chlorhexidine gluconate and ethanol dissolved in saline (CHX) for 14 days. On day 4, the chimeric ribozyme or mismatch ribozyme was intraperitoneally injected. On day 15, samples of peritoneum were obtained from the rats, and expression of TGF-beta1 mRNA and fibronectin mRNA in peritoneal tissues were evaluated by quantitative real-time PCR analysis. RESULTS: Injections of CHX significantly increased the submesothelial thickness, and increased the expression of TGF-beta1 and fibronectin mRNA in the rat peritoneum. Treatment with the chimeric ribozyme significantly reduced the CHX-induced peritoneal thickness, and expression of TGF-beta1, and fibronectin mRNA in peritoneal tissues. CONCLUSIONS: These results indicate that the chimeric DNA-RNA hammerhead ribozyme targeting TGF-beta1 mRNA has the potential for use as a gene therapy agent for EPS.