Effect of Nonsupplemented Low-Protein Diet on the Initiation of Renal Replacement Therapy in Stage 4 and 5 Chronic Kidney Disease: A Retrospective Multicenter Cohort Study in Japan.

OBJECTIVE: In subjects with chronic kidney disease (CKD), the effect of low-protein diet (LPD) is expected to alleviate uremic symptoms. However, whether LPD is effective in preventing loss of kidney function is controversial. The aim of this study was to evaluate the association between LPD and renal outcomes. METHODS: We conducted a multicenter cohort study of 325 patients who suffered CKD stage 4 and 5 with eGFR ≥10 mL/min/1.73 m,2 between January 2008 and December 2014. The primary diseases of the patients were chronic glomerulonephritis (47.7%), nephrosclerosis (16.9%), diabetic nephropathy (26.2%), and others (9.2%). The patients were divided into four groups, based on the mean protein intake (PI)/day, group 1 (n = 76): PI < 0.5 g/kg ideal body weight/day, group 2 (n = 56): 0.5 ≤ PI < 0.6 g/kg/day, group 3 (n = 110): 0.6 ≤ PI < 0.8 g/kg/day, group 4 (n = 83): PI ≥ 0.8 g/kg/day. Dietary supplementation with essential amino acids and ketoanalogues was not used. The outcome measure was occurrence of renal replacement therapy (RRT) (hemodialysis, peritoneal dialysis, renal transplantation (excluding preemptive transplantation)) and all-cause mortality until December 2018. Cox regression models were used to examine whether LPD was associated with the risk of outcomes. RESULTS: During a mean follow-up of 4.1 ± 2.2 years. Thirty-three patients (10.2%) died of all causes, 163 patients (50.2%) needed to start RRT, and 6 patients (1.8%) received a renal transplant. LPD therapy of 0.5 g/kg/day or less was significantly related to a lower risk of RRT and all-cause mortality [Hazard ratio = 0.656; 95% confidence interval, 0.438 to 0.984, P = .042]. CONCLUSIONS: These results suggest that non-supplemented LPD therapy of 0.5 g/kg/day or less may prolong the initiation of RRT in stage 4 and 5 CKD patients.

Once-weekly hemodialysis combined with low-protein and low-salt dietary treatment as a favorable therapeutic modality for selected patients with end-stage renal failure: a prospective observational study in Japanese patients.

BACKGROUND: For patients with end-stage renal failure (ESFR), thrice-weekly hemodialysis is a standard care. Once-weekly hemodialysis combined with low-protein and low-salt dietary treatment (OWHD-DT) have been rarely studied. Therefore, here, we describe our experience on OWHD-DT, and assess its long-term effectiveness. METHODS: We instituted OWHD-DT therapy in 112 highly motivated patients with creatinine clearance below 5.0 mL/min. They received once-weekly hemodialysis on a diet of 0.6 g/kg/day of protein adjusted for sufficient energy intake, and less than 6 g/day of salt intake. Serial changes in their clinical, biochemical and nutritional parameters were prospectively observed, and the weekly time spent for hospital visits as well as their monthly medical expenses were compared with 30 age, sex- and disease-matched thrice-weekly hemodialysis patients. RESULTS: The duration of successfully continued OWHD-DT therapy was more than 4 years in 11.6% of patients, 3 years in 16.1%, 2 years in 24.1% and 1 year in 51.8%. Time required per week for hospital attendance was 66.7% shorter and monthly medical expenses were 50.5% lower in the OWHD-DT group than in the thrice-weekly hemodialysis group (both p < 0.001). Patient survival rates in the OWHD-DT group were better than those in the Japan Registry (p < 0.001). Serum urea nitrogen significantly decreased; hemoglobin significantly increased; and albumin and body mass index were not significantly different from baseline values. In the OWHD-DT patients, serum albumin at 1 and 2 years after initiation of therapy was significantly higher compared with prevalent thrice-weekly hemodialysis patients. Furthermore, residual urine output was significantly higher in the OWHD-DT patients than in those receiving thrice-weekly hemodialysis (p < 0.05). Interdialytic weight gain over the course of the entire week between treatments in patients on OWHD-DT were 0.9 ± 1.0, 2.0 ± 1.3, 1.9 ± 1.2, 1.9 ± 1.5 and 1.8 ± 1.0 kg at 1, 6, 12, 18 and 24 months, respectively, though the weekly weight gain for thrice-weekly hemodialysis group (summed over all 3 treatments) was 8.6 ± 0.63 kg, p < 0.001. CONCLUSIONS: OWHD-DT may be a favorable therapeutic modality for selected highly motivated patients with ESRF. However, this treatment cannot be seen as a general maintenance strategy. TRIAL REGISTRATION: UMIN000027555 , May 30, 2017 (retrospectively registered).

Diagnosis and prevalence of protein-energy wasting and its association with mortality in Japanese haemodialysis patients.

AIM: The International Society of Renal Nutrition and Metabolism (ISRNM) has proposed the diagnostic criteria for protein-energy wasting (PEW). We studied Japanese haemodialysis (HD) patients to verify the diagnostic method, especially with respect to the body mass index (BMI) criterion, as well as the prevalence of PEW and its association with mortality. METHODS: Japanese patients receiving maintenance HD at three outpatient clinics in Tokyo (n = 210) were enrolled, and prospectively followed-up for 3 years. PEW was diagnosed at baseline, according to the four categories (serum chemistry, body mass, muscle mass and dietary intake) recommended by the ISRNM. For the category of body mass, we select a body mass index (BMI) and set up three thresholds, <18.5, <20.0 and <23.0 kg/m2 , as the diagnostic criterion. The patients who satisfied at least three out of the four categories were diagnosed as PEW. RESULTS: Protein-energy wasting, when the threshold of a BMI among the diagnostic criteria was defined as <18.5 kg/m2 , was recognized as an independent risk factor for mortality. However, PEW was not recognized as a risk factor when the BMI diagnostic criterion was set at <20.0 or <23.0 kg/m2 . Overall, 14.8% of the patients had PEW. The survival rate of PEW patients was significantly lower than that of non-PEW patients (log rank, P < 0.001). CONCLUSIONS: The diagnosis algorithm of PEW proposed by an expert panel of the ISRNM strongly associates with mortality. However, given differences in body size in Japan, we suggest to revise the BMI criterion from <23.0 kg/m2 to <18.5 kg/m2 .

Efficacy and safety of modified Yale insulin infusion protocol in Japanese diabetic patients after open-heart surgery.

To our knowledge, there is currently no insulin infusion protocol for critically ill patients especially designed for Asian diabetics although many such protocols are used in Western countries. In this study, we modified the Yale insulin infusion protocol taking into consideration the characteristics of Japanese diabetics and hospital environment. We tested the modified protocol in 40 type 2 diabetic patients after elective open-heart surgery (MY group) comparing with 35 type 2 diabetic patients under empirical blood glucose control (EC group). Analyses of 1656 blood glucose measurements during insulin infusion revealed that percentage of samples that showed achievement of target blood glucose level (80-140 mg/dl) was higher under MY (78+/-15%, n=870) than EC (57+/-23%, n=786, p<0.0001). On the other hand, the percentage of samples in which blood glucose was less than 60 mg/dl was comparable in the two groups (MY: 0.5+/-5.9 per thousand, EC: 5.1+/-18.5 per thousand). None of the patients with hypoglycemia showed significant clinical adverse effects. In conclusion, our modified Yale insulin infusion protocol is effective and safe for tight blood glucose control in Japanese diabetic patients after open-heart surgery.

Long-term efficacy of insulin glargine after switching from NPH insulin as intensive replacement of basal insulin in Japanese diabetes mellitus. Comparison of efficacy between type 1 and type 2 diabetes (JUN-LAN Study 1.2).

To assess and compare the efficacy and safety of insulin glargine as intensive replacement of basal insulin in Japanese patients with type 1 (n = 72) and type 2 (n = 46) diabetes, we switched their intensive insulin regimen from NPH plus regular or rapid-acting insulin to glargine plus bolus insulin, which included regular and rapid-acting insulin, and recorded changes in glycemic control and frequency of hypoglycemia for 18 months. The dose titration of basal and bolus insulin was based on home self-monitored blood glucose measurements and monthly HbA(1C). Mean HbA(1C) level was improved significantly at 3 months after switching to glargine plus bolus insulin regimen and these effects continued for 18 months in both type 1 and type 2 diabetes patients (HbA(1C) level: type 1: baseline 8.9 +/- 2.6%, 18 months 7.8 +/- 1.5% (p<0.05), type 2: baseline 8.2 +/- 2.6%, 18 months 7.7 +/- 1.5%. Body weight was slightly but significantly increased at 18 months only in type 2 diabetes. Total daily bolus insulin doses were not changed but basal insulin could be increased significantly after switching regimens in both types diabetes compared with baseline. The frequency of mild to moderate hypoglycemia (self-assisted episodes, blood glucose <70 mg/dl) was marginally lower with glargine but not significantly. Self-monitored fasting blood glucose level was significantly improved after switching in type 2 diabetes. Patients with the worst HbA(1C) level at baseline exhibited more than 10% improvement in HbA(1C) level after switching both type 1 and type 2 diabetes. The HbA(1C) levels of the effectively treated patients were comparable to those of ineffectively treated ones at 6 months and the same improvement was seen at 18 months. Our results suggested that insulin glargine is more effective than NPH insulin as intensive replacement of basal insulin, particularly in those Japanese patients with difficult glycemic control with NPH insulin, equally in both type 1 and type 2 diabetes.

Body protein index based on bioelectrical impedance analysis is a useful new marker assessing nutritional status: applications to patients with chronic renal failure on maintenance dialysis.

BACKGROUND: Evaluation and monitoring of nutritional status is a fundamental concept in providing nutritional care to patients with end-stage renal failure. There have been, however, few practically available indices assessing whole body protein stores of patients. METHODS: We enrolled 448 end-stage renal disease patients, 394 on maintenance hemodialysis (HD) and 54 on continuous ambulatory peritoneal dialysis (PD) in this study. 83 Age- and sex-matched subjects (controls) whose creatinine clearance was more than 70 ml/min and urinary protein excretion was less than 1.0 g/day were also recruited for comparison. To assess whole body somatic protein stores, we devised the body protein index (BPI). The volume of body protein mass was measured by multifrequency bioelectrical impedance analysis and then BPI was calculated as body protein mass (kg) divided by height in meters (m2). Based on BPI, we defined the nutritional status of the patients as normal if the value was within -10% of the mean value of control subjects, -10 to -14% as mild malnutrition, -15 to -19% as moderate malnutrition, and <-20% as severe malnutrition. RESULTS: The required time for measurement was 5.2 +/- 1.3 min and coefficient of variation of measurements was 0.8 +/- 0.2%. Among men the mean BPI in both HD and PD patients was significantly lower than those of control subjects (4.25 +/- 0.37, 4.38 +/- 0.34 vs. 4.72 +/- 0.37 kg/m2, p < 0.001). In women, BPI was significantly lower in HD patients than in control subjects (3.65 +/- 0.34 vs. 4.00 +/- 0.34 kg/m2, p < 0.033), whereas only a nonsignificant lower tendency was found in PD patients (3.83 +/- 0.39 kg/m2, p = 0.067). There were no significant differences in BPI values between diabetic and non-diabetic subjects, both in men (4.26 +/- 0.41 vs. 4.25 +/- 0.36 kg/m2) and women (3.69 +/- 0.36 vs. 3.65 +/- 0.34 kg/m2). Based on BPI nutritional categories, 113 (28.7%) of all HD patients were classified as having mild malnutrition, 57 (14.5%) as having moderate malnutrition, 40 (10.1%) as having severe malnutrition, and 184 (46.7%) were classified as normal. The patients of longer dialysis history groups showed a tendency of lower BPI compared to those of shorter dialysis history groups (p < 0.05), although the ages of the patients of the two groups did not significantly differ. No correlations were found between BPI and serum albumin or transferrin concentrations. Only weak correlations were found with albumin in male and transferrin in female HD patients. CONCLUSION: BPI calculated from measurement of multifrequency bioelectrical impedance analysis could evaluate whole body somatic protein stores, and is a potentially useful new marker assessing nutritional status in patients with chronic renal failure. Decreased body somatic protein stores, mainly due to muscle wasting, was prevalent in end-stage renal failure patients on maintenance dialysis.

Long-term effect of combination therapy with mitiglinide and once daily insulin glargine in patients who were successfully switched from intensive insulin therapy in short-term study.

We have previously reported the therapeutic efficacy of mitiglinide combined with once daily insulin glargine (mitiglinide regimen) after switching from multiple daily insulin regimen of aspart insulin and glargine (intensive insulin regimen) in inpatients with type 2 diabetes mellitus in two consecutive days. In the present study, we followed up 9 of the 15 responsive patients with these novel regimens for 6 months after discharge. The data collected from these patients were compared to those of 15 randomly chosen patients who had well matched background and received intensive insulin regimen during hospitalization which was continued after discharge. The average HbA1c level of these 9 patients with mitiglinide regimen at 6 months was 6.7 +/- 0.8% and was comparable to that of the patients with intensive insulin regimen (HbA1c = 7.0 +/- 1.0%). In conclusion, mitiglinide and insulin glargine combination therapy maintained fair glycemic control for as long as 6 months in subpopulation of Japanese patients with type 2 diabetes.

Therapeutic efficacy of mitiglinide combined with once daily insulin glargine after switching from multiple daily insulin regimen of aspart insulin and glargine in patients with type 2 diabetes mellitus.

Mitiglinide is novel class of rapid-acting insulin secretagogues, which have been widely used alone or in combination with other oral hypoglycemic drugs to improve postprandial hyperglycemia in early type 2 diabetes. While mitiglinide enhances postprandial requirement of insulin, the efficacy of mitiglinide combined with insulin has yet to be established. We investigated the efficacy of mitiglinide combined with insulin glargine, the first soluble insulin analog that has a flat and prolonged effect. After control with the intensive regimen (daily aspart insulin and glargine), 30 inpatients with type 2 diabetes were switched to premeal mitiglinide combined with once daily insulin glargine (mitiglinide regimen), and daily profiles of blood glucose level were compared under each regimen. Fifteen patients showed similar control of hyperglycemia with mitiglinide regimen and intensive insulin regimen, assessed by M value (<32), while the remaining 15 showed worsening under the mitiglinide regimen. The patients who were well controlled with mitiglinide regimen were significantly younger (51.9 +/- 16.0 years, p<0.005) and heavier (body mass index: 25.7 +/- 3.3 kg/m(2), p<0.05) than those who were not (67.9 +/- 8.7 and 23.0 +/- 3.1, respectively). Moreover, insulin doses of aspart per body weight were significantly fewer in effective group than in ineffective group. Duration of diabetes was shorter in the effective group, albeit insignificantly. Previous treatment before starting intensive insulin regimen, such as insulin and sulfonylurea, was not different between the two groups. Our results suggest that mitiglinide plus insulin glargine combination therapy is useful for lowering both fasting and postprandial hyperglycemia in a subpopulation of type 2 diabetes. The long-term effects of such treatment need to be established in future studies.

Association of socio-psychological factors with the effects of low protein diet for the prevention of the progression of chronic renal failure.

OBJECTIVE: Our objectives were to investigate the therapeutic effects of low protein diet (LPD) for chronic renal failure (CRF) in compliant patients with the diet, and to clarify the relationships to the sociopsychological factors. PATIENTS AND METHODS: Sixty-five patients (47 men and 18 women) with CRF who followed LPD (0.69 g/kg/day) for more than 3 months were recruited in this study. Compliance with the diet therapy was strictly assessed by the patients' dietary records, subsequent interviews regarding the status of daily dietary intake and estimated protein intakes calculated from urinary nitrogen excretion by 24-hour urine collections. The changes of glomerular filtration rate (GFR), serum creatinine (Cr), blood urea nitrogen (BUN), the reciprocal of serum creatinine (1/Cr), scores of Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), scales of Profile of Mood States (POMS), scores of self-efficacy and social support were investigated. RESULTS: Decline rate of GFR, elevation of Cr and BUN and reduction in 1/Cr were significantly lower in compliant patients than in noncompliant patients (p<0.05). There were no differences in SF36 scores between compliant and noncompliant patients. The POMS scales of depression/dejection were high in female noncompliant patients compared to other groups of patients (p<0.05). Self-efficacy score was higher in compliant patients than in noncompliant patients (p<0.05). Social support scores were significantly higher in male compliant patients than in others (p<0.05), and both emotional support and behavioral support showed interaction with both gender and compliance with diet therapy (p<0.05). CONCLUSION: LPD therapy is effective in suppressing the progression of CRF when it is well-adhered to. There are no correlations of this diet therapy to health-related QOL. Social support and high self-efficacy for men and high self-efficacy for women are associated with improvement of the compliance with LPD therapy, leading to good therapeutic effects.

Nutritional management of dialysis patients: balancing among nutrient intake, dialysis dose, and nutritional status.

BACKGROUND: Recommended protein intake for dialysis patients is much higher compared with allowance for normal adults. The authors tried to make a consideration on balancing among nutrient intake, dialysis dose, and nutritional status in maintenance dialysis patients. METHODS: In 57 patients, 13 on hemodialysis (HD) and 44 on continuous ambulatory peritoneal dialysis (CAPD), serum urea nitrogen (SUN), albumin, weekly creatinine clearance of CAPD, and body protein mass by multifrequency bioelectrical impedance analysis were measured. Energy intake was examined from the patients' food diary by a registered dietitian, and protein intake was estimated by both the patients' food diary and calculation of protein equivalent nitrogen appearance. RESULTS: In HD patients, predialysis SUN levels significantly correlated with the amounts of protein intake (r = 0.893; P < 0.001), and there was no correlation between post- and next predialysis SUN levels. In CAPD patients, SUN levels significantly correlated with the amounts of protein intake (r = 0.645; P < 0.001), and there was no correlation between SUN levels and weekly Ccr. The amounts of protein intake were significantly correlated with body protein mass (r = 0.365; P = 0.014), and there were significantly positive relationships between the amounts of protein intake and energy intake in both HD (r = 0.798; P < 0.001) and CAPD patients (r = 0.631; P = 0.006). CONCLUSION: Whereas higher intake of protein requires higher doses of dialysis, lower intake of protein with sufficient energy intake requires lower doses of dialysis, and both could give the same effects on nutritional status.

[Fluctuation of the rate of renal function decline associated with fluctuation of compliance with a low protein diet in patients with diabetic renal failure].

We investigated fluctuation of compliance with a low protein diet and the influence on the rate of decline in renal function. Twenty-seven patients with diabetic renal failure who were prescribed a low protein diet of 0.6 g/kg/day were followed during a period of 12 months. Dietary compliance was evaluated based on a 4-day dietary diary, interview with patients and calculation of the protein catabolic rate from 24-hour urea excretion at every hospital visit. They were judged on a 4-rank system, A(adhered over 75% of the days), B(74-50%), C(49-25%), D(less than 24%). During the twelve months, 55.5% of the patients showed fluctuation of their compliance with the diet. In 17 patients whose compliance fluctuated between rank A and B, their rate of GFR decline(ml/min/month) was significantly faster(-2.40 +/- 2.59 vs 0.99 +/- 1.41, p < 0.01), their rate of serum creatinine elevation(mg/dl/month) was significantly higher(0.90 +/- 0.79 vs -0.42 +/- 0.45, p < 0.01) and their rate of serum urea nitrogen increase(mg/dl/month) was significantly larger(15.3 +/- 12.4 vs -10.0 +/- 12.9, p < 0.01) during the period of rank B than rank A. There were no significant differences in the rates of changes in serum levels of albumin, transffering, HbA1c and body weight between the two periods. In conclusion, fluctuation of compliance with a low protein diet affects the rate of renal function decline synchronizedly in patients with diabetic renal failure.