Koichi Kanozawa

Renoprotective Effect of Pioglitazone by the Prevention of Glomerular Hyperfiltration through the Possible Restoration of Altered Macula Densa Signaling in Rats with Type 2 Diabetic Nephropathy

Background/Aims: Pioglitazone (PGZ), one of the thiazolidinediones, has been known to show renoprotective effects. In this study, we focused on the effect of PGZ on glomerular hyperfiltration (GHF), resultant glomerular injury and altered macula densa signaling as a cause of sustained GHF through modified tubuloglomerular feedback in rats with diabetic nephropathy. Methods: Kidneys from 24-week-old male OLETF rats and LET rats, nondiabetic controls, were used for the experiment. PGZ was administered (10 mg/kg/day, p.o.) for 2 weeks from 22 to 24 weeks of age in some of the OLETF rats (OLETF+PGZ). Results: Parameters relating GHF, kidney weight, creatinine clearance, urine albumin/creatinine ratio and glomerular surface were all increased in OLETF rats and partially restored in OLETF+PGZ rats. Expressions of desmin and TGF-β were also increased in OLETF rats and restored in OLETF+PGZ rats. The changes in TGF-β expression were confirmed to be independent of podocyte number. Finally, the immunoreactivity of neuronal nitric oxide synthase (nNOS) and cyclooxygenase 2 (COX-2) in the macula densa was assessed for the evaluation of macula densa signaling. Altered intensities of nNOS and COX-2 in OLETF rats were restored in OLETF+PGZ rats, which agreed with the gene expression analysis (nNOS: 100.2 ± 2.9% in LET, 64.2 ± 2.7% in OLETF, 87.4 ± 12.1% in OLETF+PGZ; COX-2: 100.8 ± 7.4% in LET, 249.2 ± 19.4% in OLETF, 179.9 ± 13.5% in OLETF+PGZ; n = 5) and the semiquantitative analysis of nNOS/COX-2-positive cells. Conclusion: PGZ effectively attenuated the GHF and hyperfiltration-associated glomerular injury in diabetic nephropathy. The restoration of altered macula densa signaling might be involved in the renoprotective effect of PGZ.

Significance of estimated salt excretion as a possible predictor of the efficacy of concomitant angiotensin receptor blocker (ARB) and low-dose thiazide in patients with ARB resistance

The purpose of this study was to assess the factors affecting the efficacy of combination therapy with losartan and thiazide, with a focus on the significance of salt excretion, via a multicenter observational study. Adult patients with essential hypertension showing therapy resistance to angiotensin receptor blocker (ARB) as a monotherapy or in combination with Ca channel blockers (CCB) were enrolled, and their previously administered ARBs were replaced with the combination tablet containing losartan (50 mg per day) and hydrochlorothiazide (12.5 mg per day). Blood pressure and biochemical parameters were monitored for a year. The baseline blood pressure (153.4±14.8/86.4±11.3 mm Hg) was significantly lowered at the 3rd month (137.3±17.4/78.2±11.1 mm Hg, n=93) and was maintained at this lower level until the 12th month (135.3±14.0/76.4±11.1 mm Hg, n=74). The baseline value of estimated salt excretion (eSE), calculated using Tanaka’s formula, differed significantly between the high and low treatment response groups, which were defined by the average change in mean blood pressure (MBP-C, −11.3 mm Hg; eSE=10.8±2.9 g per day in high responders vs. 9.2±2.3 g per day in low responders, P=0.004). Univariate and multivariate analyses showed a significant correlation between eSE and MBP-C (R=−0.288, P=0.007) and indicated the clinical effectiveness of eSE as a possible predictor for MBP-C (P=0.021). In addition, the urine Na-to-Cr ratio (NCR) demonstrated significant correlations with eSE (R=0.848, P<0.001) and MBP-C (R=−0.344, P<0.001). These results suggest that eSE or NCR could, to a certain extent, predict the efficacy of combination therapy with losartan and low-dose thiazide in patients demonstrating ARB resistance. Combination therapy with losartan and thiazide might thus be suitable for patients with a large amount of salt excretion.

Endogenous factors modified by hemodialysis may interfere with the accuracy of blood glucose-measuring device

In Japan, self‐monitoring of blood glucose (SMBG) devices are widely used both at home and in hospitals, but many analytical errors and safety concerns have been reported about the SMBG devices used in hospitals. Analytical performances of StatStrip (Nova Biomedical Corporation, MA, USA), a new point‐of‐care testing device and Glutest (Sanwa Chemical, Aichi, Japan), a routinely used SMBG device were compared in glucose measurement of pre‐ and postdialysis blood samples and we evaluated which factors in blood modified by hemodialysis affect accuracy of these devices. Subjects in this study were 44 hemodialysis patients. Blood samples were obtained from patients just before and just after the hemodialysis. Blood glucose concentrations of samples were measured by StatStrip and Glutest. Hematocrit and plasma concentrations of electrolytes, metabolites, etc. of the samples were measured in the central laboratory. StatStrip showed no difference between pre‐ and postdialysis blood samples and showed very little bias from reference method. On the other hand, Glutest showed difference between pre‐ and postdialysis samples. Although there is no problem in the data of predialysis blood samples by Glutest, however, these of the postdialysis blood samples by Glutest were >10% less than reference method. Factors in blood modified by hemodialysis such as hematocrit, uric acid, albumin, potassium, and calcium affected glucose readings by Glutest. Glucose readings by Glutest of samples from hemodialysis patients were affected by hematocrit and several factors, which were modified by hemodialysis. StatStrip is considered as a better device in dialysis hospitals.

Dysnatremia in Renal Failure

Proximal salt reabsorption in the hypertrophied tubules in the early phase of chronic renal failure (CRF) would be diminished according to the inhibited expression of proximal salt-transporting molecules, which may be facilitated by the inhibition of Na-K-ATPase expression. Results from animal models suggest that patients with early-phase CRF would easily develop hyponatremia and, in contrast, patients showing developed CRF would be more likely to show dehydration or hypernatremia. Several large-scale studies of individuals with chronic kidney disease (CKD) revealed that hyponatremia is much more common than hypernatremia in patients with earlier stages of CKD. However, patients with end-stage renal disease (ESRD) more frequently show hypernatremia than hyponatremia. These clinical trends in CKD and CRF patients are in agreement with the results of animal experiments, suggesting that salt loss might be a principal pathological setting in the early stages of CKD and that water loss could overcome the salt loss in ESRD.

Our Approaches to Selective Plasma Exchange

Plasma exchange (PE) therapy is the most commonly used treatment in Japan today. The issue with PE is that it removes coagulation factors and other essential molecules during the treatment process. Fresh frozen plasma (FFP) is used to replace the essential molecules which are lost. However, FFP can be a source of various complications. We have been researching an alternative method, selective PE, consisting of a membrane with smaller pores, which prevents large and essential molecules from being removed while removing waste from the patients blood.

Protein Energy Wasting and Sarcopenia in Dialysis Patients

As the aging of the population progresses in Japan, the nutritional problems in dialysis patients are being highlighted. Frailty is a clinical concept including body weight loss, muscle weakness, fatigability, decreased walking speed, and decreased physical activity, which means an intermediate concept between healthy subjects and disability subjects, indicating that their activities of daily living are not decreased but they cannot smoothly perform housework or exercise. Morbidity of dialysis patients is known to be high, and mortality of dialysis patients with frailty is 3 times higher. Sarcopenia is one of the principal reasons for or triggers of frailty. It is a disease setting showing decreased muscle volume and quality associated with decreased physical function or quality of life. Recent mean age at dialysis therapy induction is getting near to 70 years old in Japan. Japanese dialysis patients who are elderly and present organ failure would have a double risk for sarcopenia. Patients with advanced stages of CKD are generally given protein diet, and it has been reported that a low protein intake in dialysis patients would be a significant risk for developing sarcopenia and increasing mortality. Recently, the focus has been on protein energy wasting (PEW) - an underlying disease condition in sarcopenia or frailty. PEW is an energy wasting condition occurring in dialysis patients, and the cause of PEW is principally decreased food intake and increased catabolism. It has recently been revealed that decreased protein intake would be a risk factor for increased mortality in dialysis patients. The incidence of PEW in dialysis patients is reported to be 14%. To avoid sarcopenia and PEW leading to frailty, we should pay much more attention to an appropriate protein and calorie intake rather than restriction in dialysis patients.

Evaluation of the functions of the temporary catheter with various tip types

Introduction: A temporary catheter (TC) is used short‐term and for emergencies. There are some cases when we cannot withdraw blood immediately after inserting the catheter in our patients. The reason is said to be the tips of the TC sticking to the vascular walls.

Contents Vol. 122, 2012

Chronic Kidney Disease and Hypertension Vlado Perkovic , Sydney Adeera Levin, Vancouver, B.C. Ron Gansevoort, Groningen Acute Kidney Injury Ravi Mehta, San Diego, Calif. Nitin Kolhe, Derby Dialysis John Daugirdas, Chicago, Ill. Colin Hutchison, Hawkes Bay Casper Fraansen, Groningen Patient Subjective Experience, Healthcare Delivery and Innovation in Practice Richard Fluck, Derby Edwina Brown, London Crossover States with Non-Renal Organ Systems Chris Chan, Toronto, Ont. Tobias Breidthardt, Basel Nick Selby, Derby Transplantation Anil Chandraker, Boston, Mass. Alan Salama, London Editor-in-Chief

562 THE EFFECT TO SODIUM EXCRETION AND BLOOD PRESSURE WITH DPP-4 INHIBITORS

Background: The diabetes patients are known to be easy to present with salt sensitive hypertension. On the other hand, there is GLP-1 receptor to renal proximal tubule, and acts on sodium diuresis through NHE3. However, the effect to sodium diuresis and the blood pressure with the DPP-4 inhibitors were unknown. Aims: We examine sodium diuresis and the antihypertensive effects with the DPP-4 inhibitors by the short-term effects in the inpatients and the long-term effects in the outpatients. Methods: We gave DPP-4 inhibitor (either of sitagliptin 50–100 mg, vildagliptin 50–100 mg, alogliptin 12.5–25 mg) for patients less than 2.0 mg/dl of serum creatinine level. In the inpatients, we calculated urinary salt excretion using urine collection for 24 hours within one week around dosage. In the outpatients, we calculated sodium excretion quantity estimation level using first or second urinary in the morning, and measured the mean of home blood pressure. Results: In 23 inpatients, by the DPP-4 inhibitor dosage, urinary salt excretion significantly increased 1.8 ± 0.6 g for 24 hours. On the other hand, systolic and diastolic blood pressure significantly had decreased 6 ± 2mmHg and 5 ± 2mmHg, each. In 37 outpatients, quantity of salt excretion estimation level significantly increased 0.7 ± 0.2 g/day. The systolic blood pressure significantly had decreased 2 ± 1mmHg. The meaningful these effects were seen in alogliptin and sitagliptin, but was not seen in vildagliptin. Conclusion: By the dosage of the urine excretion type DPP-4 inhibitors for the diabetes, urinary sodium excretion increase, and blood pressure decrease.