Correlation between albuminuria and interstitial injury marker reductions associated with SGLT2 inhibitor treatment in diabetic patients with renal dysfunction.

BACKGROUND: We investigated the effects of sodium-glucose cotransporter 2 inhibitor (SGLT2i) administration focusing on its involvement in tubulo-interstitial disorders in diabetic kidney. METHODS: Enrolled patients with diabetic kidney disease received a mean dose of 52.3 mg of an SGLT2i (ipragliflozin) daily. Blood and urine were sampled at 0, 1, and 12 months (M). RESULTS: Non-renal-dysfunction patients (NRD: baseline eGFR ≥ 60 mL/min/1.73 m2, n = 12) and renal-dysfunction patients (RD: baseline eGFR < 60 mL/min/1.73 m2, n = 9) were analyzed separately. The median urine albumin-to-Cr ratio (ACR) was significantly decreased at 1 M in both groups (NRD: 163.1 at 0 M vs 118.5 mg/g Cr at 1 M, RD: 325.2 at 0 M vs 136.0 mg/g Cr at 1 M). In the RD, but not the NRD group, reduction of urine monocyte chemotactic protein-1 (MCP-1) by SGLT2i showed a significant difference between high-responders (HR: - 25.7 ± 11.4%) and low-responders (LR: 59.2 ± 17.0%), defined by ACR reduction at 1 M. Univariate analysis showed a significant correlation between the reduction of ACR and MCP-1 (R = 0.683, p = 0.042) in RD. CONCLUSION: SGLT2i exerted an anti-albuminuric effect regardless of the presence/absence of renal dysfunction. However, the anti-albuminuric effect of SGLT2i in patients with renal dysfunction appears more closely associated with amelioration of tubulo-interstitial disorders compared to patients without renal dysfunction.

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 patient's blood.

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.

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.

Down-regulation of magnesium transporting molecule, claudin-16, as a possible cause of hypermagnesiuria with the development of tubulo-interstitial nephropathy.

Tubulo-interstitial nephropathy (TIN) is a critical pathological setting for the renal prognosis, and an increase in the urine magnesium excretion is a well-known characteristic feature as one of clinical parametets for the assessment of TIN. We examined the correlation between the development of TIN and the changes in the mRNA expression of renal magnesium-transporting molecules in rats with unilateral ureter obstruction (UUO). Ureter-ligated kidney was sampled at day-0 (control), day-1 (early phase) and day-7 (late phase). The development of TIN was assessed by immunohistochemistry and the real-time PCR of fibrosis-related genes (MCP-1: 105.1 ± 14.8% on day-0, 132.9 ± 25.7% on day-1, 302.7 ± 32.7% on day-7, TGF-ß: 101.1 ± 7.6% on day-0, 93.6 ± 4.1% on day-1, 338.9 ± 20.7% on day-7) . The respective expressions of claudin-10, 14, 16, 19, and transient receptor potential (TRP) M6 as magnesium-transporting molecules were also studied. The expression of calcium sensing receptor (CaSR) as an inhibitory regulator of claudin-14 was additionally studied. The gene expression of claudin-16 was decreased in the late phase of UUO (100.2 ± 2.9% at day-0, 90.3 ± 6.3% at day-1, 36.4 ± 1.6% at day-7) which was consistent with the increased urine magnesium excretion. Immunohistochemistry showed an apparent reduction of the immunoreactivity of claudin-16 in the late phase. The expression of TRPM6 was reduced even in the early phase. The immunohistochemistry and gene expression of MCP-1 and TGF-ß showed that TIN was not apparent in the early phase but was significant in the late phase of UUO. The density of peritubular capillaries was diminished in the late phase but not in the early phase. Expression of claudin-14 and CaSR was up- and down-regulated, respectively. Our findings may indicate that the characteristic hypermagnesiuria in TIN is principally caused by the dysfunction of magnesium reabsorption in the thick ascending limb of Henle resulting from a significant decrease in the claudin-16 expression. The down-regulation might be closely related to the development of TIN.

The renoprotective effect and safety of a DPP-4 inhibitor, sitagliptin, at a small dose in type 2 diabetic patients with a renal dysfunction when changed from other DPP-4 inhibitors: REAL trial.

BACKGROUND: We conducted the multicenter, prospective, open-label study in type 2 diabetic (T2DM) patients with renal dysfunction, to clarify the efficacy and the safety in relation to renal function and glycemic control, and the economic effect when other dipeptidyl peptidase-4 (DPP-4) inhibitors were switched to a small dose of sitagliptin depending on their renal function. METHODS: Vildagliptin, alogliptin, or linagliptin received for more than 2 months were changed to sitagliptin at 25 or 12.5 mg/day depending on their renal function in 49 T2DMs. Renal function and glycemic control, and the drug cost were assessed during 6 months. RESULTS: Estimated glomerular filtration rate was not changed in patients not on hemodialysis (n = 29). The HbA1c levels were not altered in all of the patients including those on hemodialysis (n = 20). The active glucagon-like peptide-1 levels or other renal parameters were not altered significantly. There were no adverse events to be related to the drugs. The daily drug expense was reduced by 88.1 yen per patient. CONCLUSION: Switching to a small dose of sitagliptin according to the renal function in T2DM patients with renal dysfunction demonstrated the same efficacy and safety as those with other full-dose DPP-4 inhibitors, indicating a therapeutic option with a high cost performance.

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. OBJECTIVE: We evaluated examined 3 catheters with different tip shapes in a simulation circuit to assess the effect on the blood flow. METHODS: Water was circulated in the simulation circuit at 1 L/minute. Next, we inserted each TC into the model, and the TCs were connected to the dialysis circuit at 200 mL/minute. We put gold powder into the simulation circuit. We visually observed the movement of the gold power at the head of the catheter and measured the recirculation rate. RESULT: The uplift type TC was able to perform blood removal and reinfusion with the least difficulties. All recirculation rates were less than 1%. The hindrance caused by hitting a vascular wall is believed to have been reduced. CONCLUSION: With the manipulation of the catheter tip shapes, blood was able to circulate smoothly. We expect less blood clots and a decrease in sticking to the vascular wall. We plan to study these 3 catheters at clinical tests in the future.

Severe hyponatremia in a patient with schizophrenia associated with prolonged consciousness disturbance.

Hyponatremia presents with various central nervous system symptoms during its course and treatment. We treated a patient who presented with a prolonged consciousness disorder and was suspected of having complications of neuroleptic malignant syndrome and osmotic demyelination syndrome (ODS) during the treatment for his hyponatremia, which was caused by syndrome of inappropriate secretion of antidiuretic hormone (SIADH). The patient was a 30-year-old Japanese man who had been under treatment for schizophrenia. He presented with profound hyponatremia (96 mEq/L) and a consciousness disorder. Because he was taking a number of antipsychotic drugs and since psychogenic polydipsia was present along with laboratory findings, the patient was diagnosed with SIADH. However, the consciousness disorder reappeared after his serum sodium concentrations were normalized, and it persisted over a long period. Although ODS was suspected from the clinical course and imaging findings, there were several inconsistencies, such as the lack of quadriplegia. The patient also showed muscular rigidity and fever, and we, therefore, diagnosed complications of malignant hyperthermia syndrome caused by the discontinuation of all antipsychotic drugs at the time of onset. There have been no reports of complications of these two conditions, and we report this case for its clinically valuable information.

A multicenter randomized controlled trial of tonsillectomy combined with steroid pulse therapy in patients with immunoglobulin A nephropathy.

BACKGROUND: The study aim was, for the first time, to conduct a multicenter randomized controlled trial to evaluate the effect of tonsillectomy in patients with IgA nephropathy (IgAN). METHODS: Patients with biopsy-proven IgAN, proteinuria and low serum creatinine were randomly allocated to receive tonsillectomy combined with steroid pulses (Group A; n = 33) or steroid pulses alone (Group B; n = 39). The primary end points were urinary protein excretion and the disappearance of proteinuria and/or hematuria. RESULTS: During 12 months from baseline, the percentage decrease in urinary protein excretion was significantly larger in Group A than that in Group B (P < 0.05). However, the frequency of the disappearance of proteinuria, hematuria, or both (clinical remission) at 12 months was not statistically different between the groups. Logistic regression analyses revealed the assigned treatment was a significant, independent factor contributing to the disappearance of proteinuria (odds ratio 2.98, 95% CI 1.01-8.83, P = 0.049), but did not identify an independent factor in achieving the disappearance of hematuria or clinical remission. CONCLUSIONS: The results indicate tonsillectomy combined with steroid pulse therapy has no beneficial effect over steroid pulses alone to attenuate hematuria and to increase the incidence of clinical remission. Although the antiproteinuric effect was significantly greater in combined therapy, the difference was marginal, and its impact on the renal functional outcome remains to be clarified.

Adrenomedullin in peritoneal effluent expressed by peritoneal mesothelial cells.

BACKGROUND: Adrenomedullin (AM) possesses vasodilative and cell-protective properties. Glycine combines with the C-terminal of AM to form mature, physiologically active AM (mAM). AM is reportedly induced by high glucose condition in vascular endothelial or smooth muscle cells; however, little is known on how AM is activated by amidation. To investigate the behavior of AM in patients undergoing peritoneal dialysis (PD), the concentrations of AM, mAM and CA125 were measured. The mAM to AM ratio (mAM/AM ratio) was also evaluated as a marker of amidation activity. METHODS: Twenty patients were recruited for this study. The effluent at the time of the peritoneal equilibration test was collected and AM, mAM and CA125 concentrations were measured. The expression of AM in peritoneal mesothelial cells (PMCs) collected from effluent was also examined with an indirect immunofluorescent method. RESULTS: Mean values of AM and mAM in effluent were 18.1 ± 1.6 and 4.1 ± 0.3 fmol/mL, respectively. In plasma, they were 42.6 ± 3.3 and 5.6 ± 0.6 fmol/mL, respectively. AM concentrations in effluent did not correlate with plasma AM level but correlated well with the dialysate-to-plasma ratio of creatinine (D/P ratio of creatinine). Moreover, in 7 of 20 cases, concentrations of the mAM and mAM/AM ratio in effluent were higher than in plasma. In effluent, AM concentration but not the mAM/AM ratio correlated with CA125 concentration. Immunocytological study revealed diffuse, cytoplasmic expression of AM in PMCs which were collected from effluent during PD. CONCLUSION: AM is expressed by PMCs and actively amidated in the abdominal cavity of patients undergoing PD.

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.

A case of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) associated with lupus erythematosus in the central nervous system.

We report on a case of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) associated with lupus erythematosus in the central nervous system (CNS). A 73-year-old woman with essential hypertension suddenly demonstrated consciousness disturbance. Upon her admission, laboratory data showed significant hyponatremia (114 mEq/L) and a lack of body fluid loss. Diminished free water excretion (urine osmolality 684 mOsm/kg) and normal urine Na excretion (FENa 1.70 %) were consistent with the diagnosis of SIADH, which was confirmed by an inappropriately high concentration of plasma antidiuretic hormone (ADH) (15.3 pg/mL at 256 mOsm/kg of plasma osmolality). The hyponatremia was corrected by a combination of oral water intake restriction and saline infusion with furosemide administration until the 20th hospital day. Simultaneously, the presence of exudative pleural effusion in both chest cavities, suggesting the existence of pleuritis, and high titer of anti-nuclear antibody (ANA, 5120×) and anti-double-strand DNA antibody (6500 IU/mL), indicated the subclinical development of systemic lupus erythematosus (SLE), although the diagnostic criteria were not satisfied at that time. On the 34th hospital day, the sudden onset of unknown consciousness disturbance confirmed the diagnosis of SLE as CNS lupus. In previous case reports on SLE and/or SIADH, a few cases in which SLE and SIADH developed concomitantly regularly showed high immunological activities, as in our case. Some common pathophysiological bases might be involved in the concomitant appearance of those disorders.

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.

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-ß were also increased in OLETF rats and restored in OLETF+PGZ rats. The changes in TGF-ß 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.

Mature form of adrenomedullin is a useful marker to evaluate blood volume in hemodialysis patients.

We investigated the pathophysiological significance of the mature form of adrenomedullin (AM) in hemodialysis (HD) patients. Thirty-nine HD patients were enrolled and divided into two groups: those undergoing ultrafiltration (UF) during an HD session, group I; and those not undergoing UF, group II. We measured mature AM, atrial natriuretic peptide (ANP), endothelin-1, nitric oxide, cyclic guanosine 3',5'-monophosphate, and catecholamine levels at 1-hour intervals during HD sessions. On-line optical measurement of hematocrit was used to estimate change in blood volume during HD. In group II, blood volume did not change significantly during HD, nor did plasma mature AM concentrations estimated at the beginning and end of the HD treatment (3.0 +/- 0.3 and 2.8 +/- 0.2 fmol/mL, respectively). However, blood volume decreased significantly in group I patients (-7.3% +/- 0.6%), as did plasma mature AM concentrations (from 4.4 +/- 0.3 to 3.1 +/- 0.3 fmol/mL; P < 0.01). In contrast to mature AM, plasma ANP concentrations declined in both groups (from 193 +/- 32 to 87 +/- 14 pg/mL in group I and 67 +/- 12 to 46 +/- 8 pg/mL in group II). We conclude that mature AM is a useful marker to evaluate circulating blood volume in HD patients. Circulating blood volume may regulate the conversion of AM from the inactive to the mature form.