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 .

Effects of a Novel Nutritional Formula Enriched With Eicosapentaenoic Acid and Docosahexaenoic Acid Specially Developed for Tube-Fed Hemodialysis Patients.

OBJECTIVE: To evaluate the effects of a nutritional formula enriched with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in tube-fed bedridden hemodialysis patients. DESIGN: A prospective, multicenter, single-arm study. SETTING: Koyukai Memorial Hospital, Orimoto Hospital, and Chofu Hospital, Japan. SUBJECTS: Eleven tube-fed bedridden hemodialysis patients. INTERVENTION: Patients were fed a nutritional formula enriched with EPA and DHA for 12 weeks. MAIN OUTCOME MEASURES: Body weight; body mass index (BMI); serum levels of total protein, albumin, prealbumin, total cholesterol, triglyceride, and C-reactive protein (CRP); serum fatty acid composition. RESULTS: Body weight; BMI; and serum levels of total protein, albumin, total cholesterol, triglyceride, and CRP at 12 weeks were not significantly different from baseline levels. Serum prealbumin, EPA, and DHA levels significantly increased after 12 weeks of treatment. CONCLUSIONS: A nutritional formula enriched with EPA and DHA may be beneficial for nutritional management in tube-fed bedridden hemodialysis patients.

Relationship between dietary protein intake and the changes in creatinine clearance and glomerular cross-sectional area in patients with IgA nephropathy.

BACKGROUND: Dietary protein intake (PI) induces glomerular hyperfiltration and reduced dietary PI can be effective in preserving kidney function. However, there is limited information regarding the relationship between dietary PI and glomerular histological changes in chronic kidney disease. We investigated the relationship between changes in dietary PI and both the changes in creatinine clearance and glomerular histomorphometry in adult patients with IgA nephropathy (IgAN). METHODS: A total of 24 consecutive adult patients with biopsy-confirmed IgAN were enrolled and glomerular histomorphometric variables and clinical variables were investigated. The main clinical variables were differences in creatinine clearance (Ccr) (dCcr) and in PI (dPI) which were calculated by subtracting PI and Ccr values in patients on a controlled diet during hospitalization for kidney biopsy from the respective values in patients on daily diets as outpatients. These values of PI were estimated from urinary urea excretion measured by 24-h urine collection. The main renal histomorphometric variable was glomerular tuft area (GTA) (µm(2)). RESULTS: dCcr positively correlated with dPI (r = 0.726, P < 0.001). GTA correlated positively with dPI (r = 0.556, P = 0.013). Multiple regression analysis showed that dPI was independently associated with both dCcr and GTA. Additionally, GTA positively correlated with dietary PI as outpatients (r = 0.457, P = 0.043). CONCLUSION: Changes in dietary PI were associated with the changes in glomerular filtration rate. Furthermore, histomorphometric findings suggested that a greater dietary PI can affect the glomerular size at the time of the initial diagnostic biopsy for IgAN.

Combined therapy with peritoneal dialysis and hemodialysis: a multicenter retrospective observational cohort study in Japan.

BACKGROUND/AIMS: Combining peritoneal dialysis (PD) and hemodialysis (HD) has been common treatment option in Japan. METHODS: In this retrospective, multicenter, observational study, the clinical characteristics and outcomes of 104 patients (57 ± 11 years, males 72%) who had switched from PD alone to combined therapy with PD and HD were studied. Clinical parameters were measured at baseline and after 3 months of combined therapy. RESULTS: At baseline, urine volume, dialysate-to-plasma ratio of creatinine (D/P Cr), and total Kt/V were 150 ml/day (range: 0-2,000 ml/day), 0.67 ± 0.11, and 1.8 ± 0.4, respectively. During the first 3 months of combined therapy, body weight, urine volume, serum creatinine level, and D/P Cr decreased, whereas hemoglobin levels increased. CONCLUSIONS: In patients where PD does not result in acceptable outcomes, combined therapy with PD and HD may have potential benefits in terms of dialysis adequacy and hydration status. Video Journal Club "Cappuccino with Claudio Ronco" at http://www.karger.com/?doi=368389

[Validity of the assessment of urinary protein excretion by spot urine in patients with chronic kidney disease].

AIM: We investigate the validity of the assessment of urinary protein excretion by spot urine samples collected by different methods in outpatients with chronic kidney disease (CKD). SUBJECTS AND METHODS We obtained 24-hour urine and two spot urine samples, including the first morning urine and daytime urine in 159 CKD patients. Urinary protein excretion was assessed by the protein/creatinine ratio from spot urine samples (morning: m-UP (g/gCr), daytime: d-UP (g/gCr) ]. We examined the correlations and the differences among m-UP, d-UP and the actual urinary protein excretion obtained by 24-hour urine (a-UP(g/day) . RESULTS: Significant correlations were found between m-UP and a-UP, and between d-UP and a-UP (r = 0.88, 0.85; p < 0.001). Correlations between m-UP and a-UP were greater relative to those between d-UP and a-UP in patients with less than 3.5 g/day of a-UP and in patients with CKD stages 1 to approximately 3. The percent difference between m-UP and a-UP was--16.0 +/- 40.5%, and that between d-UP and a-UP was 27.1 +/- 72.9%. The absolute value of the percent difference between d-UP and a-UP tended to be greater than that between m-UP and a-UP (34.9 +/- 25.9% vs. 49.9 +/- 59.9%, p = 0.06). CONCLUSION: Urinary protein/creatinie ratio of the first morning urine is better approximate the urinary protein excretion obtained by 24-hour urine compared with that of spot urine in the daytime.

Clinical significance of microscopic haematuria in diabetic nephropathy in type 2 diabetes patients with overt proteinuria.

AIM: Although some patients with diabetic nephropathy with overt proteinuria have microscopic haematuria, the pathological characteristics and clinical significance related to microscopic haematuria have not yet been clarified. The aim of the present study was to clarify the pathological characteristics and clinical significance of microscopic haematuria. METHODS: Eighty-four type 2 diabetes patients with overt proteinuria and biopsy-confirmed diabetic nephropathy were enrolled. The clinical and histological findings were compated between the patients with persistent haematuria (group 1, n=25) and those with persistent non-haematuria (group 2, n=23) after renal biopsy. The association between persistent haematuria and renal outcome at 5 years was examined. Histological scoring was made according to the original system and that of Tervaert et al. RESULTS: Thirty-six patients (43%) had microscopic haematuria at the time of renal biopsy. Age was significantly smaller and blood pressure was significantly greater in group 1 than in group 2 (age: group 1, 56 ± 10 years; group 2, 62 ± 9 years; P=0.03, systolic blood pressure: group 1, 152 ± 16 mm Hg; group 2, 140 ± 16 mm Hg; P=0.01). There were no significant differences in histological parameters between the two groups. A logistic regression model demonstrated that arteriolar hyalinosis was significantly associated with persistent haematuria (OR=2.81; P=0.04). There were no significant differences in changes in reciprocal serum creatinine and rates of doubling of serum creatinine after renal biopsy between the two groups. CONCLUSION: Although arteriolar hyalinosis was associated with persistent haematuria, the clinical significance of microscopic haematuria was minor in diabetic nephropathy in type 2 diabetes patients with overt proteinuria.

Phosphate handling by end-stage kidneys and benefits of residual renal function on phosphate removal in patients on haemodialysis.

AIM: We investigated the handling of phosphate by end-stage kidneys and the contribution of residual renal function (RRF) to phosphate homeostasis in haemodialysis patients. METHODS: Blood and 24 h urinary specimens were obtained from 79 consecutive chronic haemodialysis patients with a urinary output greater than 100 mL/day. Thirty-five patients with a glomerular filtration rate (GFR) ≥ 3.0 mL/min were included as group A, and 44 patients with GFR < 3.0 mL/min as group B. Additionally, the whole dialysed fluids during a session of haemodialysis were collected from another nine patients. Concentrations of phosphate, creatinine, urea nitrogen, intact parathyroid hormone (iPTH) and fibroblast growth factor 23 (FGF-23) were measured. RESULTS: Twenty-four hour urinary phosphate excretion (UPE) was 283 ± 115 and 139 ± 57 mg/day (9.1 ± 3.5 and 4.5 ± 1.8 mmol/day) in groups A and B, respectively. Tubular reabsorption of phosphate (TRP) was 39.2 ± 13.3 and 31.7 ± 13.6% in groups A and B, respectively (P = 0.02). UPE significantly correlated with GFR (r = 0.85, P < 0.001) and PTH (r = 0.44, P < 0.001), but not with FGF-23, in the entire patient population. The correlation between UPE and intact PTH levels was absent in group B. Weekly UPE in group A was significantly greater (P < 0.001), while that in group B was similar to the amount of phosphate removed by a haemodialysis session. CONCLUSIONS: Urinary phosphate excretion by end-stage kidneys depends more on GFR than diminishing TRP. The action of PTH on the kidneys remains until GFR decreases to as low as 3 mL/min. Residual renal function plays a significant role in phosphate elimination, and it is possible that FGF-23 no longer acts effectively to excrete phosphate in the urine in these patients.

Histological predictors for renal prognosis in diabetic nephropathy in diabetes mellitus type 2 patients with overt proteinuria.

AIM: Although several clinical risk factors for end-stage renal disease in diabetic nephropathy are known, the pathological findings that may help predict renal prognosis have not yet been defined. METHODS: We enrolled 69 diabetes mellitus type 2 patients with overt proteinuria and biopsy-confirmed diabetic nephropathy with mesangial expansion, and retrospectively examined the association of histological and clinical findings with renal outcome. The median follow-up duration was 52 months. Histological scoring was made according to that of Tervaert et al. Patients were divided into four groups according to glomerular classification (class 2a, mild mesangial expansion, n=11; class 2b, severe mesangial expansion without nodular sclerosis, n=15; class 3, nodular sclerosis, n=36; class 4, global glomerulosclerosis observed in more than 50% of glomeruli, n=7). Interstitial and vascular lesions were scored for each patient. A renal event was defined as a condition requiring the initiation of chronic dialysis or doubling of the serum creatinine level. RESULTS: Cox proportional hazard analysis showed that the glomerular classes were not significant variables, while interstitial fibrosis, tubular atrophy and interstitial inflammation were independent variables associated with renal end-point (HR: 3.36 (95% confidence interval: 1.21-9.32), 4.74 (1.26-17.91)). There were no significant differences in the renal survival rates between the glomerular classes 2a and 2b combined group and the glomerular class 3 group (P=0.17, log-rank test). CONCLUSION: Interstitial lesions but not glomerular lesions were a significant predictor for renal prognosis in diabetic nephropathy in type 2 diabetes patients with overt proteinuria.

Association of home blood pressure variability with progression of chronic kidney disease.

OBJECTIVE: Home blood pressure (HBP) has been found to be a predictor of the progression of chronic kidney disease (CKD). The objective of this study is to clarify the clinical significance of day-by-day HBP variability on the progression of CKD. METHODS: We recruited 135 patients with stage 3-5 CKD, who performed daily HBP measurements, every morning and evening over 7 consecutive days and recorded every 6 months, with a follow-up of 36 months. We examined the associations between the variables of blood pressure (BP) variability [SD, coefficient of variation (CV), average real variability (ARV)], and renal outcomes. RESULTS: No significant correlations were found between the SD values, the CV values, the ARV values of each BP measurement, and the change in estimated glomerular filtration rate on multivariate regression analysis (ß of SD, CV, and ARV of morning systolic BP: 0.04, 0.04, and 0.02; P=0.69, 0.63, and 0.20, respectively). None of these variables of each BP measurement showed a significant risk of renal events on multivariate Cox proportional hazards analysis (hazard ratios of SD, CV, and ARV of morning systolic BP: 0.99 (95% confidence intervals: 0.80-1.23), 0.97 (0.72-1.31), and 1.01 (0.83-1.24); P=0.94, 0.86, and 0.92, respectively). CONCLUSION: Day-by-day BP variability as assessed by HBP measurements had no significant association with the progression of CKD.

Prevalence and clinical characteristics of restless legs syndrome in chronic kidney disease patients.

OBJECTIVE: To clarify the prevalence of restless legs syndrome (RLS) in the chronic kidney disease (CKD) population and determine the relationship between severity of renal dysfunction and risk of RLS as well as the impact of the disorder on mood and sleep disturbance, we conducted a questionnaire survey followed by face-to-face interviews with Japanese CKD patients. METHODS: We sent a questionnaire battery including demographics items, the National Institutes of Health/International RLS Study Group (IRLSSG) consensus questionnaire, the Center for Epidemiological Studies Depression Scale, and the Pittsburgh Sleep Quality Index to eligible CKD patients (n=514) and age- and sex-matched controls (n=535). Structured interviews were performed for the diagnosis of RLS. RESULTS: The prevalence of positive RLS in the CKD subjects was significantly higher than that in the controls (3.5% vs. 1.5%, p=0.029). The proportion of renal failure (RF) in CKD subjects with RLS was significantly higher than in those without RLS, and multiple logistic regression analysis revealed that the presence of RLS symptoms was associated only with the existence of RF. In addition, the presence of both RLS and CKD was significantly associated with the presence of depression and sleep disturbance. CONCLUSIONS: The risk of RLS in the CKD population was higher than that in the general population and increased with the progression of renal dysfunction. Additionally, the existence of RLS might play a role in an increased risk for developing depression and sleep disturbance in the CKD population.

Triple therapy with single daily dose of cyclosporine in Japanese patients with idiopathic membranous nephropathy.

OBJECTIVE: The optimal therapeutic approach to patients with idiopathic membranous nephropathy (IMN) remains controversial. In this study, we assessed the efficacy of single daily dose cyclosporine (CsA) combined with low-dose prednisolone (PSL) and an angiotensin II receptor blocker (ARB) in patients with IMN. METHODS: We studied 13 nephrotic patients (8 men, 5 women) with IMN diagnosed on biopsy. An initial single daily dose of 2 mg/kg, but not exceeding 150 mg, CsA was given for 12 months, tapered by a 25 mg reduction every 2 months. An initial twice-daily dose of 0.5 mg/kg PSL was given for 2 months and was also tapered. An ARB was given to all patients and the same dosage was used throughout the study. Patients were followed up for 6 to 66 months. RESULTS: Nine patients achieved complete remission at 6.7±2.9 months, and incomplete remission was obtained in the remaining patients. After a follow-up period of 32.7±20.0 months, their serum creatinine and estimated glomerular filtration rate values were similar to baseline levels. The 9 patients who completed the treatment course have not relapsed. Moreover, there were no adverse effects requiring discontinuation of this triple therapy. CONCLUSION: A single daily dose of CsA combined with a low dose of PSL and an ARB in new-onset nephrotic patients with IMN induced a high remission rate of nephrotic syndrome, with a low incidence of relapse and a low risk of adverse effects. The triple therapy and prospective follow-up shows potential as a treatment approach for patients with IMN.

Ratio of urinary potassium to urinary sodium and the potassium and edema status in nephrotic syndrome.

OBJECTIVE: This study aimed to evaluate the relevance of ratios of urinary potassium to urinary sodium + potassium (U(K)/U(Na + K)) to edema status in minimal-change nephrotic syndrome (MCNS). METHODS: We retrospectively studied 26 adults with newly diagnosed MCNS with significant pitting edema. On the basis of mean value (0.46±0.21) of U(K)/U(Na + K) determined from spot urine samples on admission, patients were classified into 2 groups. RESULTS: On admission, 12 of 26 patients had U(K)/U(Na + K) >0.46 (0.65±0.16, Group H), 14 patients had U(K)/U(Na + K) <0.46 (0.29±0.08, Group L). The level of serum albumin was similarly decreased in these 2 groups. Noteworthy were lower urine volume, fractional excretion of sodium (FENa), serum sodium, and higher hematocrit in the group H as compared with the group L. The group H had a shorter mean time required from onset of edema to hospitalization, and tended to have a longer mean time to complete remission than group L. High U(K)/U(Na + K) levels in group H decreased significantly after remission, eventually becoming equal to those of group L (0.24±0.05 vs. 0.25±0.05). CONCLUSION: U(K)/U(Na + K) determined from spot urine sample on admission relates to laboratory or clinical indices to distinguish edema status in adult patients with MCNS.