Masanori Abe

Antidiabetic Agents in Patients with Chronic Kidney Disease and End-Stage Renal Disease on Dialysis: Metabolism and Clinical Practice

Numerous drugs with different mechanisms of action and different pharmacologic profiles are being used with the aim of improving glycemic control in patients with type 2 diabetes. Therapeutic options for patients with type 2 diabetes and chronic kidney disease (CKD) are limited because a reduced glomerular filtration rate results in the accumulation of certain drugs and/or their metabolites. Conventional oral hypoglycemic agents, such as sulfonylurea (SU), are not suitable due to the risk of prolonged hypoglycemia; furthermore, metformin is contraindicated for moderate to advanced CKD. Therefore, in order to achieve good glycemic control, insulin injection therapy remains the mainstay of treatment in diabetic patients with moderate to advanced CKD, particularly in those receiving dialysis therapy. However, some agents have been used even in patients with CKD. Repaglinide and mitiglinide are rapid- and short-acting insulinotropic SU receptor ligands. They are rarely accompanied by hypoglycemia, and are attractive therapeutic options even in the dialysis population. In addition, alpha-glucosidase inhibitors are rarely accompanied by hypoglycemia and are administered without dose adjustments in dialysis patients. However, the National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines recommended that alpha-glucosidase inhibitors should be avoided in patients with advanced stage CKD and on dialysis. Furthermore, mitiglinide is not currently used in the US. Thus, recommended oral antidiabetic agents differ between countries. Moreover, dipeptidyl peptidase-4 inhibitors and incretin mimetics are new antihyperglycemic agents, which may be used more frequently in the future in patients with type 2 diabetes and CKD. Here, we describe the pharmacokinetics, metabolism, clinical efficacy, and safety of oral Antidiabetic agents for patients with CKD, including those receiving dialysis.

Benidipine reduces albuminuria and plasma aldosterone in mild-to-moderate stage chronic kidney disease with albuminuria

Benidipine inhibits both L- and T-type Ca channels, and has been shown to dilate the efferent arterioles as effectively as the afferent arterioles. In this study, we conducted an open-label and randomized trial to compare the effects of benidipine with those of amlodipine on blood pressure (BP), albuminuria and aldosterone concentration in hypertensive patients with mild-to-moderate stage chronic kidney disease (CKD). Patients with BP⩾130/80 mm Hg, with estimated glomerular filtration rate (eGFR) of 30–90 ml min−1 per 1.73 m2, and with albuminuria>30 mg per g creatinine (Cr), despite treatment with the maximum recommended dose of angiotensin II receptor blockers (ARBs) were randomly assigned to two groups. Patients received either of the following two treatment regimens: 2 mg per day benidipine, which was increased up to a dose of 8 mg per day (n=52), or 2.5 mg per day amlodipine, which was increased up to a dose of 10 mg per day (n=52). After 6 months of treatment, a significant and comparable reduction in the systolic and diastolic BP was observed in both groups. The decrease in the urinary albumin to Cr ratio in the benidipine group was significantly lower than that in the amlodipine group. Although plasma renin activity was not different in the two groups, plasma aldosterone levels were significantly decreased in the benidipine group. Moreover, urinary Na/K ratio was significantly decreased in the benidipine group but remained unchanged in the serum. It may be concluded that benidipine results in a greater reduction of plasma aldosterone and albuminuria than amlodipine, and that these effects are independent of BP reduction.

Haemodialysis-induced hypoglycaemia and glycaemic disarrays

In patients with diabetes receiving chronic haemodialysis, both very high and low glucose levels are associated with poor outcomes, including mortality. Conditions that are associated with an increased risk of hypoglycaemia in these patients include decreased gluconeogenesis in the remnant kidneys, deranged metabolic pathways, inadequate nutrition, decreased insulin clearance, glucose loss to the dialysate and diffusion of glucose into erythrocytes during haemodialysis. Haemodialysis-induced hypoglycaemia is common during treatments with glucose-free dialysate, which engenders a catabolic status similar to fasting; this state can also occur with 5.55 mmol/l glucose-containing dialysate. Haemodialysis-induced hypoglycaemia occurs more frequently in patients with diabetes than in those without. Insulin therapy and oral hypoglycaemic agents should, therefore, be used with caution in patients on dialysis. Several hours after completion of haemodialysis treatment a paradoxical rebound hyperglycaemia may occur via a similar mechanism as the Somogyi effect, together with insulin resistance. Appropriate glycaemic control tailored for patients on haemodialysis is needed to avoid haemodialysis-induced hypoglycaemia and other glycaemic disarrays. In this Review we summarize the pathophysiology and current management of glycaemic disarrays in patients on haemodialysis.

The dipeptidyl peptidase-4 inhibitor alogliptin improves glycemic control in type 2 diabetic patients undergoing hemodialysis

Objectives: The potent and selective dipeptidyl peptidase-4 (DPP-4) inhibitor alogliptin improves glycemic control in patients with type 2 diabetes through incretin hormone-mediated increases in both α- and β-cell responsiveness to glucose. In this study, the efficacy and safety of alogliptin in type 2 diabetic patients undergoing hemodialysis (HD) were evaluated. Methods: A prospective, open-label study of 30 patients (male/female: 24/6; mean age: 69.7 ± 1.7 years) with type 2 diabetes who were undergoing HD without insulin injection therapy was conducted. Patients were administered 6.25 mg/day alogliptin and efficacy and safety were determined by monitoring clinical and laboratory parameters during the 48-week study period. Results: After 48 weeks, alogliptin had decreased postprandial plasma glucose levels from 212 ± 8 mg/dL baseline to 156 ± 7 mg/dL, hemoglobin A1c levels from 7.1 ± 0.2% baseline to 6.3 ± 0.2% and glycated albumin (GA) levels from 25.6 ± 0.6% baseline to 20.7 ± 0.4% (all p < 0.0001). Alogliptin efficacy did not differ according to median age or body mass index, but the GA reduction was significantly greater in the antidiabetic agents-naïve group. The magnitude of GA reduction was baseline GA-dependent, being greater at higher baseline GA levels. No serious adverse effects, such as hypoglycemia or liver impairment, were observed in any patient. Conclusion: Alogliptin as monotherapy or in combination with other oral antidiabetic agents improved glycemic control and was generally well tolerated in patients with HD over a 48-week period.

Clinical study of influenza-associated rhabdomyolysis with acute renal failure.

AIMS Influenza-associated rhabdomyolysis induces renal failure with a fatal outcome. The aim of this study is to evaluate the clinical features, diagnosis, and treatment efficacy of influenza-associated rhabdomyolysis patients with acute renal failure (ARF). MATERIALS AND METHODS The subjects included 6 patients who had presented with rhabdomyolysis and ARF due to influenza infection on admission to our university hospital and its 2 affiliated hospitals between January 2002 and February 2004. We retrospectively examined the cases. RESULTS All the patients (n = 6) were males, and none of them had received an influenza vaccine. The viruses were identified as influenza A (n = 5) and B (n = 1). Muscular weakness was observed in many cases (n = 5), whereas pain or tenderness was observed in only 1 case (n = 1). For anuric or oliguric patients (n = 4), blood purification therapy was performed, while for patients in whom the urine volume was normal (n = 2), conservative therapy was administered. CONCLUSION Careful medical attention is necessary when patients have muscle pain and weakness. Early recognition of rhabdomyolysis allows prompt institution of an appropriate therapy that includes blood purification and may minimize the renal dysfunction associated with this disorder.

Comparison of the antiproteinuric effects of the calcium channel blockers benidipine and amlodipine administered in combination with angiotensin receptor blockers to hypertensive patients with stage 3-5 chronic kidney disease

Benidipine, an L- and T-type calcium channel blocker, dilates both efferent and afferent arterioles and reduces glomerular pressure. Thus, it may exert renoprotective effects. We conducted an open-labeled, randomized trial to compare the blood pressure (BP)-lowering effect and antiproteinuric effect of benidipine with those of amlodipine in hypertensive patients with moderate-to-advanced-stage chronic kidney disease (CKD) (stages 3–5). These patients were already being administered the current maximum recommended doses of angiotensin receptor blockers (ARBs). Patients with BP ⩾140/90 mm Hg, despite treatment with the maximum recommended dose of ARBs, were randomly assigned to two groups. The patients received either of the following treatment regimens: 4 mg day−1 of benidipine, which was increased up to a dose of 16 mg day−1 (B group; n=24), and 2.5 mg day−1 of amlodipine, which was increased up to a dose of 10 mg day−1 amlodipine (A group; n=23). After 6 months of treatment, a significant and comparable reduction in the systolic and diastolic BP was seen in both groups. The decrease in the urinary protein to creatinine ratio in the B group was significantly lower than that in the A group. Benidipine exerted antiproteinuric effect to a greater extent than did amlodipine, even in patients with diabetic nephropathy. We conclude that the addition of benidipine, rather than amlodipine, ameliorates urinary protein excretion in hypertensive patients with CKD who are already being administered ARBs. Therefore, we propose a combination therapy with benidipine and ARBs, even for patients with moderate-to-advanced-stage CKD.

Plasma Insulin is Removed by Hemodialysis: Evaluation of the Relation Between Plasma Insulin and Glucose by Using a Dialysate With or Without Glucose

Abstract:  The aim of the present study was to evaluate the alteration in plasma immunoreactive insulin (IRI) and glucose concentrations due to hemodialysis (HD) treatment by using a dialysate with or without glucose in HD patients. We divided the patients into three groups: non‐diabetic patients (n‐DM group), well‐controlled diabetic patients (HbA1c <7.0% [w‐DM group]), and poorly‐controlled diabetic patients (HbA1c≥7.0% [p‐DM group]). Using a dialysate with a glucose concentration of 100 mg/dL (glu(+)‐dialysate) and a glucose‐free dialysate (glu(−)‐dialysate), we studied the daily profiles of plasma glucose in the three groups. We measured the levels of plasma glucose and IRI at three time points (predialysis and 2 h and 4 h after the initiation of dialysis) at pre(A) and postdialyzer (V) sites in HD patients. There was a significant increase in the daily profiles of the plasma glucose level from the time before dinner until bedtime in both the w‐DM and p‐DM groups, when comparing the values on an HD day with those on a non‐HD day. In the p‐DM group, the use of the glu(−)‐dialysate resulted in a significant hyperglycemia in the evening hours when compared with the use of the glu(+)‐dialysate. In the DM group, the use of the glu(+)‐dialysate resulted in a significant decrease in the plasma glucose and IRI levels during HD. However, in the n‐DM group, there was no difference in the plasma glucose levels during HD. On the other hand, the use of a glucose‐free dialysate led to a significant decrease in the plasma glucose and IRI levels during HD in all groups. The plasma IRI levels decreased significantly between the A and V sites at each point in all groups irrespective of the glucose concentration of the dialysate. The present study confirmed that the concentration of not only glucose but also IRI had decreased during the passage of the plasma through the dialyzer. In HD patients with diabetes, the glucose content of the hemodialysis solution plays an important role in preventing acute hypoglycemia and hyperglycemia on HD days.

Mineral Metabolic Abnormalities and Mortality in Dialysis Patients

The survival rate of dialysis patients, as determined by risk factors such as hypertension, nutritional status, and chronic inflammation, is lower than that of the general population. In addition, disorders of bone mineral metabolism are independently related to mortality and morbidity associated with cardiovascular disease and fracture in dialysis patients. Hyperphosphatemia is an important risk factor of, not only secondary hyperparathyroidism, but also cardiovascular disease. On the other hand, the risk of death reportedly increases with an increase in adjusted serum calcium level, while calcium levels below the recommended target are not associated with a worsened outcome. Thus, the significance of target levels of serum calcium in dialysis patients is debatable. The consensus on determining optimal parathyroid function in dialysis patients, however, is yet to be established. Therefore, the contribution of phosphorus and calcium levels to prognosis is perhaps more significant. Elevated fibroblast growth factor 23 levels have also been shown to be associated with cardiovascular events and death. In this review, we examine the associations between mineral metabolic abnormalities including serum phosphorus, calcium, and parathyroid hormone and mortality in dialysis patients.

Elevated macrophage migration inhibitory factor (MIF) levels in the urine of patients with focal glomerular sclerosis

The pathogenesis of focal glomerular sclerosis (FGS) is poorly understood. Macrophage migration inhibitory factor (MIF) is a potent pro‐inflammatory cytokine released from T cells and macrophages, and is a key molecule in inflammation. To examine further the possible role of MIF in FGS, we measured MIF levels in the urine. The purpose of the present study was to evaluate the involvement of MIF in FGS. Urine samples were obtained from 20 FGS patients. The disease controls included 40 patients with minimal‐change nephrotic syndrome (MCNS) and membranous nephropathy (MN). A group of healthy subjects also served as controls. Biopsies were performed in all patients prior to entry to the study. The samples were assayed for MIF protein by a sandwich enzyme‐linked immunosorbent assay (ELISA). The levels of MIF in the urine of FGS patients were significantly higher than those of the normal controls and patients with MCNS and MN. In contrast, the levels of urinary MIF (uMIF) in patients with MCNS and MN did not differ significantly from normal values. In the present study, attention also focused on the relationship between uMIF levels and pathological features. Among the patients with FGS, uMIF levels were significantly correlated with the grade of mesangial matrix increase and that of interstitial fibrosis. There was also a significant correlation between uMIF levels and the number of both intraglomerular and interstitial macrophages. Although the underlying mechanisms remain to be determined, our study presents evidence that urinary excretion of MIF is increased in FGS patients with active renal lesions.

Combination therapy with mitiglinide and voglibose improves glycemic control in type 2 diabetic patients on hemodialysis

Objective: Mitiglinide, a rapid- and short-acting insulinotropic sulfonylurea receptor ligand, exhibits hypoglycemic action unlike other sulfonylureas. The efficacy of the combination of mitiglinide and α-glucosidase inhibitors for diabetic patients on hemodialysis (HD) has not been prospectively evaluated; therefore, we evaluated the efficacy and safety of mitiglinide in these patients. Research design and methods: We performed an open-label randomized study with 36 type 2 diabetics with poor glycemic control on HD and receiving daily doses of voglibose (0.9 mg). The patients were randomly assigned to two groups: a combination-therapy group (mitiglinide group), mitiglinide initial dose 7.5 – 15 mg titrated to 30 mg daily and constant daily dose 0.9 mg of voglibose, and a monotherapy group (control group), constant daily dose 0.9 mg of voglibose alone. The efficacy of the treatment was determined by monitoring plasma glucose, hemoglobin A1c (HbA1c), and glycated albumin (GA) levels and using homeostasis model assessment of insulin resistance (HOMA-IR). Safety and tolerance were determined by monitoring clinical and laboratory parameters. Results: The final dose of mitiglinide was 22.9 ± 8.9 (mean ± s.d.) mg (0.41 mg/kg) daily. Mitiglinide reduced fasting plasma glucose and GA levels after 4 weeks and HbA1c levels after 8 weeks. Triglyceride levels and HOMA-IR values also decreased significantly after mitiglinide treatment. No significant changes in blood pressure levels or serious adverse effects such as hypoglycemia or liver impairment were observed. Conclusions: This study suggests a combination therapy of mitiglinide and voglibose may have potential for the treatment of diabetics on HD. Due to the small sample size used, further studies should be performed, particularly to assess the safety of mitiglinide treatment.