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.

Difficulty removing dialysis cuff catheter after its adhesion to the right atrium.

We describe the case of an elderly Japanese female who had experienced diabetic nephropathy since the year 20xx and had been undergoing dialysis treatment while receiving vascular access interventional therapy (VAIVT) for arteriovenous fistula (AVF) occlusion. The patient visited the clinic/hospital in 20xx+10 with the AVF occlusion; emergency VAIVT was performed but blood flow could not be resumed. The patient was not admitted and was treated as an outpatient, and thus a cuff catheter (Split stream catheter: SST28 cm, Medcomp) was inserted. An infection developed and was successfully treated with antibiotics. The dialysis treatment continued without issue. One year after the cuff catheter's insertion, the patient was admitted due difficulty breathing. Despite continued dialysis treatment with the catheter, the patient died 15 days post-admission. The removal of the catheter proved to be difficult. An autopsy was approved, and the area around the catheter was examined. The adhesion of the catheter to the right atrium was observed, but no infection was detected in the bloodstream. This case illustrates that dialysis with the use of a cuff catheter can be effective.

Assessment of an Automatic Hot Water Sterilizing System-Equipped Dialysis Supply Device's Circuit Degradation, 7 Years Postinstallment.

At most dialysis clinics in Japan, a central dialysis fluid delivery system (CDDS) is used primarily to provide consistent treatment to patients. We incorporated hot water disinfection to a CDDS over a 7 year period, after which we assessed the dialysis purification levels. We observed that adequate levels had been maintained. We rated the internal circuits of the device at the 7 year mark, comparing the insides of both the used and unused new Synflex tubing, silicone blades, Teflon tubing, silicone rubber tubing, and stainless steel parts. No bacteria or contamination (such as endotoxins) was detected, and no degradation or damage were observed. Even after the auto-hot water disinfection system was installed, no internal tubing degradation due to hot water or mechanical issues have occurred, and the system's dialysis fluid purification levels have been maintained.

Combined hemophagocytic syndrome and thrombotic microangiopathy due to mixed infection with influenza virus and pneumococcal pneumonia.

Development of hemophagocytic syndrome and thrombotic microangiopathy due to community-acquired pneumonia is rare, but delayed management of these complications can lead to a poor prognosis. Infection by both Streptococcus pneumoniae and influenza virus can cause these complications; thus, physicians should pay attention to them when treating influenza-associated pneumococcal pneumonia.

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.

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.

Methods We Currently Use for Home Hemodialysis Management.

There are approximately 1,330,000 chronic renal failure patients in Japan, and over 30,000 patients are introduced to dialysis therapy annually. By the end of 2015, there were over 320,000 dialysis patients in Japan. Various groups have been working hard to educate all people involved including the patient, their families, doctors, nurses, and caregivers on three important topics: hemodialysis, peritoneal dialysis, and kidney transplantation. Recently, there has been a growing interest in home hemodialysis. Although peritoneal dialysis has existed in Japan for a long time, the number of peritoneal dialysis patients in Japan has not been increasing. Only 3% of the total number of dialysis treatments done here are peritoneal. Despite these circumstances, home hemodialysis therapy has been gaining attention in Japan, which is a big breakthrough. We are at the frontier of improving dialysis; however, introducing home hemodialysis has been a difficult obstacle to overcome. Here, we would like to present our methods of introducing home hemodialysis and how we have dealt with this challenge.

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.

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.

How to monitor vascular access in our hospital.

BACKGROUND: The number of dialysis patients in Japan has amounted to approximately 310,000. Most of the patients undergo hemodialysis. The reason why they can undergo hemodialysis is because maintaining and managing vascular access (VA) has improved. Recently, thanks to the progress of medical equipment, a variety of monitoring systems have been developed. It is important to make good use of these monitoring systems. RESULTS: In our hospital, we have been monitoring with an ultrasonic device and HD02. We measure blood flow of brachial artery with an ultrasonic device during nondialysis treatment. We examine real blood flow and blood recirculation with HD02 and evaluate the function of VA during dialysis. CONCLUSIONS: In order to provide good dialysis care, good use of monitoring devices of VA is significant.

The Impact of Buttonhole Cannulation on Patients and Staff in Hemodialysis Facilities.

The two reasons that patients desire buttonhole cannulation are avoidance of puncture pain and extension of arteriovenous fistula life. Despite the desire to receive buttonhole cannulation by many patients, medical staff at most local hemodialysis facilities tend to hesitate to implement the cannulation method. This method is used on patients in the dialysis unit at Saitama Medical Center, but tends to be discontinued for those patients upon their transfer to local hemodialysis facilities. Medical staff members of one local hemodialysis facility report the percentage of patients on the buttonhole method was 53% in 2007, but that it sharply decreased to 17% in 2013. Hesitation by local hemodialysis facilities to adopt the buttonhole method is due to, but not limited to, several factors. These factors include the frequently occurring trampoline effect, the difficulty of removing scabs, formation of a false buttonhole track, and the pain from insertion of a dull needle. Perceived differences in the value of buttonhole cannulation may potentially affect communication between patients and staff in local hemodialysis facilities.

Clinical significance of fractional magnesium excretion (FEMg) as a predictor of interstitial nephropathy and its correlation with conventional parameters.

BACKGROUND: Elevated urine Mg excretion and its correlation with histological damage in tubulo-interstitial nephropathy (TIN) were reported. Here we investigated the clinical significance of the fractional excretion of Mg (FEMg) for the prediction of TIN. METHODS: We enrolled and assessed 94 adult patients with various renal diseases diagnosed principally by renal biopsy. RESULTS: Our stratified analysis based on the value of the conventional TIN parameter N-acetylglucosaminidase (NAG) excretion showed that the high-NAG index group (more than median value of NAG-to-Cr ratio, n = 47) demonstrated significantly high FEMg values (p = 0.017). A univariate analysis revealed a significant correlation between the FEMg and the NAG index (R = 0.60) but not for other parameters. A multivariate regression analysis confirmed the significance of the FEMg as an effective predictor of the NAG index. The FEMg showed a significant correlation with the estimated glomerular filtration rate (eGFR) in the patients with eGFR ≤ 30 mL/min. The correlation of FEMg with the NAG index was not observed in the primary glomerulonephritis patients but was apparent in the patients with hypertensive nephrosclerosis or interstitial nephritis. CONCLUSION: Our findings may indicate that the combination of the FEMg and the NAG index can provide a specific, sensitive assessment for TIN in patients without renal insufficiency.

Downregulation of transient receptor potential M6 channels as a cause of hypermagnesiuric hypomagnesemia in obese type 2 diabetic rats.

We assessed the expression profile of Mg(2+)-transporting molecules in obese diabetic rats as a cause of hypermagnesiuric hypomagnesemia, which is involved in the development of insulin resistance, hypertension, and coronary diseases. Kidneys were obtained from male Otsuka Long-Evans Tokushima fatty (OLETF) and Long-Evans Tokushima Otsuka (LETO) obese diabetic rats at the ages of 16, 24, and 34 wk. Expression profiles were studied by real-time PCR and immunohistochemistry together with measurements of urine Mg(2+) excretion. Urine Mg(2+) excretion was increased in 24-wk-old OLETF rats and hypomagnesemia was apparent in 34-wk-old OLETF rats but not in LETO rats (urine Mg(2+) excretion: 0.16 ± 0.01 µg·min(-1)·g body wt(-1) in 24-wk-old LETO rats and 0.28 ± 0.01 µg·min(-1)·g body wt(-1) in 24-wk-old OLETF rats). Gene expression of transient receptor potential (TRP)M6 was downregulated (85.5 ± 5.6% in 34-wk-old LETO rats and 63.0 ± 3.5% in 34-wk-old OLETF rats) concomitant with Na(+)-Cl(-) cotransporter downregulation, whereas the expression of claudin-16 in tight junctions of the thick ascending limb of Henle was not different. The results of the semiquantitative analysis of immunohistochemistry were consistent with these findings (TRPM6: 0.49 ± 0.04% in 16-wk-old LETO rats, 0.10 ± 0.01% in 16-wk-old OLETF rats, 0.52 ± 0.03% in 24-wk-old LETO rats, 0.10 ± 0.01% in 24-wk-old OLETF rats, 0.48 ± 0.02% in 34-wk-old LETO rats, and 0.12 ± 0.02% in 34-wk-old OLETF rats). Gene expression of fibrosis-related proinflammatory cytokines as well as histological changes showed that the hypermagnesiuria-related molecular changes and tubulointerstitial nephropathy developed independently. TRPM6, located principally in distal convoluted tubules, appears to be a susceptible molecule that causes hypermagnesiuric hypomagnesemia as a tubulointerstitial nephropathy-independent altered tubular function in diabetic nephropathy.

Release from glomerular overload by the addition of low-dose thiazide in patients with angiotensin receptor blocker-resistant hypertension.

BACKGROUND/AIMS: This multicenter, prospective, observational study assessed the renoprotective effects of losartan/thiazide combination therapy in terms of lowering the estimated glomerular filtration rate (eGFR). METHODS: Adult patients with angiotensin receptor blocker (ARB)-resistant essential hypertension (n = 104) were enrolled and switched to combination therapy with losartan (50 mg/day) and hydrochlorothiazide (12.5 mg/day). RESULTS: eGFR values declined significantly during the first 3 months, and changes in eGFR were assessed according to tertiles of the eGFR decrease ratio at 3 months. Only the high eGFR decrease (1st tertile) group showed significantly greater decreases in baseline eGFR and albumin-to-creatinine ratio (ACR) during the first 3 months. Additionally, the assessment according to tertiles of the baseline eGFR showed a signifcant decrease in eGFR and ACR during the first 3 months in the high baseline eGFR (1st tertile) group, but not in the moderate (2nd tertile) and low baseline eGFR (3rd tertile) groups. CONCLUSION: The present results revealed that losartan/thiazide combination therapy attenuated glomerular overload, indicating that this therapy may provide glomerular protection in patients with an elevated GFR without causing prolonged damage to renal function.

Prevention of lipopolysaccharide-induced peritoneal damage by eplerenone in rats undergoing peritoneal dialysis.

BACKGROUND: Bacterial peritonitis in patients undergoing peritoneal dialysis (PD) is a major cause of therapy interruption due to peritoneal insufficiency. Here we studied the effect of a selective mineralocorticoid receptor (MR) blocker, eplerenone, on the prevention of peritoneal damage.
 METHODS: Male Sprague-Dawley rats were treated with a daily infusion of human use PD solution (100 mL/kg i.p., PD group, n = 5), or with PD solution and intermittent intraperitoneal injections of lipopolysaccharide (LPS group, n = 5) or with LPS and eplerenone (100 mg/kg/d, po, Ep group, n = 5) for 4 weeks. Peritoneal samples were subjected to assessment following the peritoneal equilibration test (PET). RESULTS: Histological observations revealed that LPS treatment resulted in significant peritoneal thickening associated with increased ED-1-positive cell infiltration and the number of transforming growth factor (TGF)-ß1-positive cells, and that eplerenone reduced these changes. LPS administration also evoked significant upregulation of monocyte chemotactic protein-1 and TGF-ß1, which were inhibited by eplerenone. PET revealed that ultrafiltration and transperitoneal osmotic diffusion were significantly impaired by LPS and restored by eplerenone. Increased value of the mass transfer area coefficients for creatinine values was also recovered by Ep (0.10 ± 0.01 in the PD, 0.14 ± 0.02 in the LPS and 0.08 ± 0.0 in the Ep groups). Immunostaining for von Willebrand factor showed a significant increase by LPS and its restoration by Ep.
 CONCLUSIONS: Ep effectively diminished LPS-induced peritoneal insufficiency. A selective blockade of MR might prevent peritoneal insufficiency associated with bacterial peritonitis.

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.