Long-term effectiveness of a primary care practice facilitation program for chronic kidney disease management: an extended follow-up of a cluster-randomized FROM-J study.

BACKGROUND: Practice facilitation program by multidisciplinary care for primary care physicians (PCPs) is expected to improve chronic kidney disease (CKD) outcomes, but there is no clear evidence of its long-term effectiveness. We have previously performed a cluster-randomized controlled trial for 3.5 years (the Frontier of Renal Outcome Modifications in Japan (FROM-J) study) with two arms-group A without the program and group B with the program. We aimed to assess the long-term effectiveness of the practice facilitation program on CKD outcomes via an extended 10-year follow-up of the FROM-J study. METHODS: We enrolled patients who were in the FROM-J study. The primary composite endpoint comprised cardiovascular disease (CVD), renal replacement therapy initiation and a 50% decrease in the estimated glomerular filtration rate (eGFR). The secondary endpoints were survival rate, eGFR decline rate and collaboration rate between PCPs and nephrologists. RESULTS: The occurrence of the primary composite endpoint tended to be lower in group B (group A: 27.1% versus group B: 22.1%, P = 0.051). Furthermore, CVD incidence was remarkably lower in group B (group A: 10.5% versus group B: 6.4%, P = 0.001). Although both mortality and the rate of eGFR decline were identical between both groups, the eGFR decline rate was significantly better in group B than in group A only in patients with stage G3a at enrollment (group A: 2.35 ± 3.87 mL/min/1.73 m2/year versus group B: 1.68 ± 2.98 mL/min/1.73 m2/year, P = 0.02). The collaboration rate was higher in group B. CONCLUSIONS: The CKD practice facilitation program for PCPs reliably decreases CVD events and may reduce the progression of cases to end-stage kidney disease.

SGLT2 inhibitor and loop diuretic induce different vasopressin and fluid homeostatic responses in nondiabetic rats.

Loop diuretics are commonly used diuretics in the treatment of fluid retention but induce hypovolemia-related renal dysfunction. Na+-glucose cotransporter 2 (SGLT2) inhibitors induce osmotic diuresis, but body fluid volume is maintained by stimulating vasopressin-induced fluid intake and collecting duct water reabsorption as previously reported in diabetic rats. We aimed to test the hypothesis that unlike SGLT2 inhibitors, loop diuretics lack activation of similar fluid homeostatic mechanisms. Nondiabetic male Sprague-Dawley rats were treated daily by oral gavage with vehicle, the SGLT2 inhibitor ipragliflozin (5 mg/kg), or the loop diuretic furosemide (50 mg/kg) and monitored in metabolic cages for 2 or 7 days. Ipragliflozin and furosemide similarly increased urine volume on day 2. This was associated with increased serum Na+ concentration, urine vasopressin excretion, fluid intake, and solute-free water reabsorption in response to ipragliflozin but not to furosemide. Ipragliflozin maintained fluid balance (fluid intake - urine volume) on day 2 and total body water measured by bioimpedance spectroscopy and serum creatinine on day 7. In comparison, furosemide decreased fluid balance on day 2 and decreased total body water and increased serum creatinine on day 7. Furosemide, but not ipragliflozin, increased plasma renin activity, and systolic blood pressure was similar among the groups. In conclusion, the osmotic diuresis of the SGLT2 inhibitor increased serum Na+ concentration and the vasopressin-related stimulation of fluid intake and renal water retention maintained fluid balance, whereas the loop diuretic did not engage the compensatory vasopressin system. The data suggest differences in vasopressin and fluid homeostatic responses between SGLT2 inhibitors and loop diuretics.NEW & NOTEWORTHY In nondiabetic rats, the Na+-glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin increased vasopressin-related stimulation of fluid intake and free water reabsorption and maintained fluid balance and serum creatinine, whereas the loop diuretic furosemide reduced vasopressin and induced a negative fluid balance followed by a subsequent increase in serum creatinine. This study suggests that differences in vasopressin secretion in response to a SGLT2 inhibitor or loop diuretic may contribute to differences in body fluid status and subsequent renal function.

Comparative Impact of Isolated Ultrafiltration and Hemodialysis on Fluid Distribution: A Bioimpedance Study.

INTRODUCTION: Isolated ultrafiltration (IUF) is an alternative treatment for diuretic-resistant patients with fluid retention. Although hemodialysis (HD) predominantly decreases extracellular water (ECW), the impact of IUF on fluid distribution compared with HD remains unclear. METHODS: We compared the effect of HD (n = 22) and IUF (n = 10) sessions on the body fluid status using a bioimpedance analysis device (InBody S10). RESULTS: The total ultrafiltration volume was similar between HD and IUF (HD 2.5 ± 0.3 vs. ICF 2.1 ± 0.3 L/session, p = 0.196). The reduction rate of ECW was significantly higher than that of intracellular water (ICW) after HD (ECW -7.9% ± 0.8% vs. ICW -3.0% ± 0.9%, p < 0.001) and IUF (ECW -5.8% ± 0.9% vs. ICW -3.6% ± 0.8%, p = 0.048). However, the change in the ratio of ECW to total body water in HD was significantly larger than that in IUF (HD -3.2% ± 0.3% vs. ICF -1.1% ± 0.4%, p < 0.001). The reduction rates in serum tonicity (effective osmolality) were higher after HD than after IUF (HD -1.8% ± 0.5% vs. IUF -0.6% ± 0.2%, p = 0.052). Among the components of effective osmolality, the reduction rates of serum K+ and glucose levels after HD were significantly higher than those after IUF (serum K+: HD -30.5% ± 1.6% vs. IUF -0.5% ± 3.8%, p < 0.001; serum glucose: HD -15.4% ± 5.0% vs. IUF 0.7% ± 4.8%, p = 0.026), while the serum Na+ level was slightly and similarly reduced (HD -0.8% ± 0.4% vs. IUF -0.8% ± 0.4%, p = 0.500). The reduction in the osmolal gap value (measured osmolality-calculated osmolarity) was significantly greater after HD sessions than after IUF sessions (HD -12.4 ± 1.4 vs. IUF 2.0 ± 1.0 mOsm/kg, p = 0.001). CONCLUSION: The extracellular fluid reduction effect of HD is stronger than that of IUF. The different changes in effective osmolality and osmolal gap after HD and IUF sessions may be related to the different effects of HD and IUF on fluid distribution.

Effects of the sodium-glucose cotransporter 2 inhibitor dapagliflozin on fluid distribution: A comparison study with furosemide and tolvaptan.

AIM: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are an antihyperglycemic drug with diuretic properties. We recently reported that an SGLT2 inhibitor ameliorated extracellular fluid expansion with a transient increase in urinary Na+ excretion. However, the effects of SGLT2 inhibitors on fluid distribution in comparison to conventional diuretics remain unclear. METHODS: Forty chronic kidney disease patients with fluid retention (average estimated glomerular filtration rate 29.2 ± 3.2 mL/min per 1.73 m2 ) were divided into the SGLT2 inhibitor dapagliflozin (DAPA), loop diuretic furosemide (FR) and vasopressin V2 receptor antagonist tolvaptan (TLV). The body fluid volume was measured on days 0 and 7 using a bioimpedance analysis device. RESULTS: In all three groups, body weight was significantly and similarly decreased, and urine volume numerically increased for 7 days. Bioimpedance analysis showed that the changes in intracellular water were similar, but that there were significant changes in the extracellular water (ECW) (DAPA -8.4 ± 1.7, FR -12.5 ± 1.3, TLV -7.4 ± 1.5%, P = 0.048). As a result, the change in the ratio of ECW to total body water in the DAPA group was significantly smaller than that in the FR group, but numerically larger than that in the TLV group (DAPA -1.5 ± 0.5, FR -3.6 ± 0.5, TLV -0.5 ± 0.4%, P < 0.001). CONCLUSION: Sodium-glucose cotransporter 2 inhibitor DAPA predominantly decreased the ECW with a mild increase in urine volume, but the change in the ECW/total body water was smaller than that in patients treated with FR, and larger than that in patients treated with TLV, suggesting that the effects of SGLT2 inhibitors on fluid distribution may differ from those of conventional diuretics.

Unmasking a sustained negative effect of SGLT2 inhibition on body fluid volume in the rat.

The chronic intrinsic diuretic and natriuretic tone of sodium-glucose cotransporter 2 (SGLT2) inhibitors is incompletely understood because their effect on body fluid volume (BFV) has not been fully evaluated and because they often increase food and fluid intake at the same time. Here we first compared the effect of the SGLT2 inhibitor ipragliflozin (Ipra, 0.01% in diet for 8 wk) and vehicle (Veh) in Spontaneously Diabetic Torii rat, a nonobese type 2 diabetic model, and nondiabetic Sprague-Dawley rats. In nondiabetic rats, Ipra increased urinary excretion of Na+ (UNaV) and fluid (UV) associated with increased food and fluid intake. Diabetes increased these four parameters, but Ipra had no further effect, probably because of its antihyperglycemic effect, such that glucosuria and, as a consequence, food and fluid intake were unchanged. Fluid balance and BFV, determined by bioimpedance spectroscopy, were similar among the four groups. To study the impact of food and fluid intake, nondiabetic rats were treated for 7 days with Veh, Ipra, or Ipra+pair feeding+pair drinking (Pair-Ipra). Pair-Ipra maintained a small increase in UV and UNaV versus Veh despite similar food and fluid intake. Pair-Ipra induced a negative fluid balance and decreased BFV, whereas Ipra or Veh had no significant effect compared with basal values. In conclusion, SGLT2 inhibition induces a sustained diuretic and natriuretic tone. Homeostatic mechanisms are activated to stabilize BFV, including compensatory increases in fluid and food intake.

Decline in estimated glomerular filtration rate is associated with risk of end-stage renal disease in type 2 diabetes with macroalbuminuria: an observational study from JDNCS.

BACKGROUND: There is increased interest in surrogate endpoints for clinical trials of chronic kidney disease. METHODS: In this nationwide observational study of 456 patients with type 2 diabetes and clinically suspected diabetic nephropathy followed for a median of 4.2 years, we evaluated the association between estimated glomerular filtration rate (eGFR) and albuminuria at baseline or during follow-up and risk of ESRD. RESULTS: Low eGFR (<60 mL/min/1.73 m2) and macroalbuminuria at enrollment were independently associated with risk of ESRD. In patients with macroalbuminuria, both ≤-50% change and -50 to -30% change in eGFR over 1 and 2 years were predictive of ESRD. The higher cut point (≥50% decline in eGFR) was more strongly predictive but less common. Remission of macroalbuminuria to normo-/microalbuminuria at 1 and 2 years was associated with a lower incidence of ESRD than no remission; however, it was not a determinant for ESRD independently of initial eGFR and initial protein-to-creatinine ratio. CONCLUSION: These results suggest that a ≥30% decline in eGFR over 1 or 2 years adds prognostic information about risk for ESRD in patients with type 2 diabetes and macroalbuminuria, supporting the consideration of percentage decline in eGFR as a surrogate endpoint among macroalbuminuric cases in type 2 diabetes. On the other hand, our study suggests that additional analyses on the relationship between remission of macroalbuminuria and risk of ESRD are needed in type 2 diabetes.

Partial Delignification as Pretreatment for Nanoporous Carbon Material from Biomass.

For the pretreatment in order to nano prepare porous carbon from biomass such as bamboo, a mixture of acetic acid and hydrogen peroxide was used for the partial delignification of bamboo. The pretreatment should be effective for the removal of lignin because the lignin percentage after the pretreatment depended on the treatment time and the treatment temperature. For the concentration of the mixture used for the pretreatment in this study, a small amount of lignin (ca. 2 wt%) remained even after a sufficiently-long treatment time. The BET specific surface area of the carbon material prepared by the heat treatment at 800 degrees C for 1 h under flowing N2 was related to the pretreatment conditions, and the specific surface areas of the samples were found to be related to the lignin percentage. The removal of lignin while maintaining the microstructure derived from plant tissue could be the reason for the local maximum of the specific surface area at ca. 5% of the lignin.

The association between soluble intercellular adhesion molecule-1 levels in drained dialysate and peritoneal injury in peritoneal dialysis.

BACKGROUND: Chronic inflammation of the peritoneum causes peritoneal injury in patients on peritoneal dialysis. Intercellular adhesion molecule-1 and its circulating form, soluble intercellular adhesion molecule-1, play pivotal roles in inflammation. However, their role in peritoneal injury is unclear. METHODS: We measured changes in intercellular adhesion molecule-1 expression in the peritoneum of a peritoneal injury model in rats. The associations between soluble intercellular adhesion molecule-1 levels in drained dialysate and the solute transport rate (D/P-Cr and D/D0-glucose) determined by the peritoneal equilibration test, and matrix metalloproteinase-2 levels in drained dialysate were investigated in 94 peritoneal drained dialysate samples. RESULTS: Intercellular adhesion molecule-1 expression was increased in the peritoneum of rats with peritoneal injury. Soluble intercellular adhesion molecule-1 levels in drained dialysate were significantly positively correlated with D/P-Cr (r = .51, p < .01) and inversely correlated with D/D0-glucose (r = -.44, p < .01). They were also significantly positively correlated with matrix metalloproteinase-2 levels in drained dialysate (r = .86, p < .01). CONCLUSIONS: Intercellular adhesion molecule-1expression is increased in the peritoneum of a peritoneal injury model in the rat, and soluble intercellular adhesion molecule-1 levels in drained dialysate are associated with peritoneal injury in patients on peritoneal dialysis. These results suggest that soluble intercellular adhesion molecule-1 could be a novel biomarker of peritoneal injury in patients on peritoneal dialysis.

Subclinical growth of an arteriovenous fistula associated with renal biopsy: a case report.

BACKGROUND: Renal biopsy is not free from complications and patients who undergo this procedure are usually hospitalized to receive intensive care for several days after biopsy. In contrast, after this period, routine follow-up to detect biopsy-associated complications is rarely scheduled, unless the patient develops a clinical manifestation. We describe a case of marked enlargement of arteriovenous fistula in the kidney that occurred many years after renal biopsy. In contrast to the previous cases requiring interventional radiology, our patient showed subclinical growth of fistula over about nine years. CASE PRESENTATION: A 24-year-old man with a history of percutaneous renal biopsy was hospitalized for interventional radiology. Gross hematuria emerged shortly after biopsy, but completely disappeared with administration of hemostatic agents and bed rest. Subsequently, the patient had few symptoms for many years. A giant fistula (a gourd-shaped mass, size 26 × 22 and 12 × 11 mm) was unexpectedly detected by ultrasonography performed for examination of an unrelated disorder (slight elevation of serum transaminase) at 9 years after the original biopsy. The fistula was successfully treated with radiological intervention. Thus, subclinical development of complications associated with renal biopsy should be considered, even in an uneventful course. CONCLUSIONS: This case provides a platform to discuss the importance of long-term follow-up of patients after renal biopsy despite of its difficulty.

HIF-1α mediates Hypoxia-induced epithelial-mesenchymal transition in peritoneal mesothelial cells.

The epithelial-to-mesenchymal transition (EMT) of peritoneal mesothelial cells plays a pivotal role in the development of peritoneal fibrosis. The pathological effects of hypoxia on mesothelial cell EMT have not been fully elucidated. In this study, we, therefore, investigated the effects of hypoxia on EMT in mesothelial cells. Human mesothelial (MeT-5A) cells and primary-cultured rat mesothelial cells were cultured under hypoxic conditions (1% O(2)) for up to 72 h. Changes in cell type were then determined by investigating changes in morphology and in expression of epithelial (E-cadherin and occludin) and mesenchymal (fibronectin-1, vimentin and α-smooth muscle actin) cell markers. In some cases, MeT-5A cells were cultured under hypoxic conditions with a HIF-1α inhibitor and then assessed for changes in morphology and for altered expression of signaling molecules, such as HIF-1α, Snail-1, vascular endothelial growth factor (VEGF), and matrix metalloproteinase-2 (MMP-2). Levels of HIF-1α, Snail-1, VEGF, and MMP-2 in Met-5A cells were increased by hypoxia. Levels of epithelial cell markers were decreased and those of mesenchymal cell markers were increased. Cell morphology also changed from a cobblestone-like monolayer to spindle-shaped fibroblast-like cells in response to hypoxia. Inhibition of HIF-1α signaling by a HIF-1α inhibitor abrogated these changes. The cell marker and morphological changes induced by hypoxia were also observed in primary-cultured rat mesothelial cells. We can conclude that hypoxia induces EMT in mesothelial cells by activating HIF-1α. This finding indicates that hypoxia has pivotal roles in the development of peritoneal fibrosis in peritoneal dialysis patients.

Attenuation of methylglyoxal-induced peritoneal fibrosis: immunomodulation by interleukin-10.

Peritoneal fibrosis (PF), a serious pathophysiology of peritoneal dialysis (PD), is implicated in various types of chronic inflammation. In the present study, we examined the benefits of interleukin (IL)-10, which exerts anti-inflammatory effects, in an experimental rat model of methylglyoxal (MGO)-induced PF. We injected an adeno-associated virus (AAV) vector encoding rat IL-10 or enhanced green fluorescent protein (GFP) into male Sprague-Dawley rats at 6 weeks of age. Four weeks later, the rats received continuous peritoneal injections of conventional PD fluid (PDF) with MGO for 3 weeks. Then, the peritoneal histology and the expression levels of fibrogenic mediators and proinflammatory cytokines were analyzed. The rats demonstrating persistent IL-10 expression showed significantly reduced fibrous peritoneal thickening compared with those with GFP expression. The infiltration of macrophages, the expression of tumor necrosis factor-α, IL-1ß, IL-6, transforming growth factor-ß1, Snail, and matrix metalloproteinase 2 genes as well as the proliferation of mesenchymal-like mesothelial cells augmented by MGO were all significantly suppressed by IL-10 expression. IL-10 also abrogated the extent of MGO-induced bowel adhesions mimicking a cocoon-like mass. Our findings provide valuable insight into the potential benefit of immunomodulation with IL-10 as one potentially effective therapeutic strategy for preventing the onset of peritoneal injury resulting in PF.

Involvement of P2Y12 receptor in vascular smooth muscle inflammatory changes via MCP-1 upregulation and monocyte adhesion.

Antiplatelet drugs, frequently used for cardiovascular events with thrombotic involvement, are also regarded as possible promising agents for cardiovascular primary prevention. The roles of P2Y12, an ADP receptor and the target of thienopyridine antiplatelet drugs, are not satisfactorily known in the vascular wall. We investigated the hypothesis that vascular smooth muscle cell (VSMC) P2Y12 is involved in vascular wall inflammatory changes by upregulating monocyte chemoattractant protein-1 (MCP-1) and promoting monocyte adhesion. ADP at 10(-5) M induced a 3.6 ± 0.3-fold upregulation of MCP-1 mRNA in cultured rat VSMCs, which was significantly inhibited by R-138727, the active metabolite of P2Y12 inhibitor prasugrel and siRNAs against P2Y12. ADP also induced MCP-1 protein upregulation, which was diminished by R-138727 and P2Y12 siRNAs. JNK (c-Jun NH2-terminal kinase) inhibition attenuated ADP-induced MCP-1 mRNA and protein upregulation. R-138727 and P2Y12 siRNAs inhibited ADP-induced JNK activation. The reactive oxygen species (ROS) inhibitors N-acetylcysteine (NAC), diphenyleneiodonium (DPI), and Tempol also diminished MCP-1 upregulation and JNK activation induced by ADP. ADP induced MCP-1 promoter activation, which was inhibited by R-138727 and P2Y12 siRNAs. Nuclear factor-κB (NF-κB) consensus sites in the MCP-1 promoter region were involved in this activation. ADP-induced NF-κB pathway activation, examined by a plasmid containing multiple NF-κB sites, was diminished by P2Y12 inhibition. For cellular function analysis, stimulation of VSMC with ADP increased subsequent THP-1 monocyte adhesion. P2Y12 siRNAs and CCR2 antagonism diminished this ADP-induced monocyte adhesion. These data suggested that ADP, via the VSMC P2Y12 receptor, induces vascular inflammatory changes by upregulating MCP-1 and promoting monocyte adhesion.

ASC in renal collecting duct epithelial cells contributes to inflammation and injury after unilateral ureteral obstruction.

Inflammation plays a crucial role in the pathophysiological characteristics of chronic kidney disease; however, the inflammatory mechanisms underlying the chronic kidney disease process remain unclear. Recent evidence indicates that sterile inflammation triggered by tissue injury is mediated through a multiprotein complex called the inflammasome. Therefore, we investigated the role of the inflammasome in the development of chronic kidney disease using a murine unilateral ureteral obstruction (UUO) model. Inflammasome-related molecules were up-regulated in the kidney after UUO. Apoptosis-associated speck-like protein containing a caspase recruitment domain deficiency significantly reduced inflammatory responses, such as inflammatory cell infiltration and cytokine expression, and improved subsequent renal injury and fibrosis. Furthermore, apoptosis-associated speck-like protein containing a caspase recruitment domain was specifically up-regulated in collecting duct (CD) epithelial cells of the UUO-treated kidney. In vitro experiments showed that extracellular adenosine triphosphate (ATP) induced inflammasome activation in CD epithelial cells through P2X7-potassium efflux and reactive oxygen species-dependent pathways. These results demonstrate the molecular basis for the inflammatory response in the process of chronic kidney disease and suggest the CD inflammasome as a potential therapeutic target for preventing chronic kidney disease progression.

Validation of the Japanese histologic classification 2013 of immunoglobulin A nephropathy for prediction of long-term prognosis in a Japanese single-center cohort.

BACKGROUND: A new Japanese histologic classification (JHC) of immunoglobulin A nephropathy (IgAN) for prediction of long-term prognosis was proposed in 2013. The goal of this study was to validate the JHC system in a Japanese single-center cohort. METHODS: A retrospective study was conducted in 198 Japanese adult patients with IgAN. Clinical findings including blood pressure, urinary protein, estimated glomerular filtration rate (eGFR), and outcomes were evaluated in these patients. The glomerular lesion percentage score (GLPS) [number of glomeruli with cellular crescents, fibrocellular crescents, global sclerosis, segmental sclerosis, or fibrous crescents/number of total obtained glomeruli × 100 (%)] was assessed in each patient and categorized into histologic grades (HGs) of HG1 (<25 %), HG2 (25-49 %), and HG3/4 (≥50 %). Associations of GLPS (HG) with disease progression (50 % eGFR decline or end-stage renal disease requiring dialysis) within 10 years after biopsy and the rate of annual eGFR decline were examined. RESULTS: During a median follow-up period of 12.0 years after biopsy, disease progression occurred in 12.8 % (12/94) of HG1 patients, 32.3 % (21/65) of HG2 patients, and 46.2 % (18/39) of HG3/4 patients. The risk of disease progression was significantly higher in the HG2 and HG3/4 groups than in the HG1 group (odds ratios: 3.3 and 5.9 vs. 1). A higher GLPS was significantly associated with a higher risk of disease progression and a greater annual eGFR decline. CONCLUSION: The newly proposed JHC system 2013 based on GLPS (HG) was well correlated with long-term prognosis in our cohort of Japanese adult patients with IgAN.

[Comparison of benefits to non-dialysis CKD patients between darbepoetin alpha and epoetin beta pegol].

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) are the mainstay of treatment for renal anemia in chronic kidney disease (CKD) patients. However, the difference in hematopoietic effect between darbepoetin alfa (DA) and continuous erythropoiesis receptor activator (CERA) has remained unclear in non-dialysis CKD patients. Another purpose of this study was to analyze the red blood cells indices under treatment with these two ESAs in ESA-naïve CKD patients. METHODS: This study was designed as a multicenter retrospective observational investigation, and included 61 patients receiving DA (group DA) and 36 patients receiving CERA (group CERA) for at least six months. Relative effect of these ESAs was determined by comparing means of the individual monthly average of the area under the curve above the initial level of hemoglobin (Hb), hematocrit (Hct), and red blood cell count (RBC) with the trapezoidal rule, which are maintenance ratios. Serial changes in mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) were also evaluated. RESULTS: No differences were found in the mean ratios of Hb, Hct, and RBC, and maintenance ratios of these parameters. The ratio of MCH in group CERA was decreased compared with that in group DA. Subsequent decrease in MCV was also remarkable in group CERA. CONCLUSIONS: It is speculated that iron demand increased during the administration of CERA, which was suggested by changes in the red cell indices. Reticulocyte indices and iron-related parameters could provide a more detailed explanation and the significance of iron supplementation during administration of CERA should be clarified when compared with other types of ESA.

Peritoneal fibrosis induced by intraperitoneal methylglyoxal injection: the role of concurrent renal dysfunction.

BACKGROUND: Peritoneal fibrosis (PF) is a serious pathophysiology of peritoneal dialysis (PD). An ongoing focus of research is the potential fibrogenic nature of methylglyoxal (MGO) in conventional PD fluid (PDF). The aim of the current study was to explore the effects of the uremic milieu on the promotion of PF by MGO using rats with adenine-induced renal failure (RF). METHODS: Adenine-treated Sprague-Dawley rats were randomly assigned to receive continuous peritoneal injections of PDF with or without MGO for three weeks or were left untreated for the same duration. Rats without RF were also assigned to three groups. The peritoneal histology and expression levels of type I collagen, transforming growth factor-ß1 (TGF-ß1), α-smooth muscle actin (αSMA), Snail, matrix metalloproteinase-2 (MMP-2), advanced glycation end-products (AGEs) and the receptor for AGE (RAGE) were then analyzed. RESULTS: Peritoneal treatment with 5 mM MGO accelerated the fibrous peritoneal thickening progression promoted by exposure to standard PDF in the rats with RF, but not in the rats with a normal renal function. Treatment with MGO significantly augmented the proliferation of mesenchymal-like mesothelial cells, accumulation of AGE, de novo expression of αSMA and RAGE and gene expression of type I collagen, TGF-ß1, Snail and MMP-2, whereas both MGO and RF alone had, at most, marginal effects on the changes in these biological parameters. CONCLUSIONS: In the present study, the adverse effects of MGO on the peritoneum became more prominent under conditions of a uremic milieu. These findings imply that MGO and uremia act cooperatively to induce PF.

Primary care physicians' own exercise habits influence exercise counseling for patients with chronic kidney disease: a cross-sectional study.

BACKGROUND: The appropriate exercise counseling for chronic kidney disease (CKD) patients is crucial to improve their prognosis. There have been few studies about exercise counseling by primary care physicians for CKD patients. We investigated primary care physicians' exercise counseling practices for CKD patients, and the association of these physicians' own exercise habits with exercise counseling. METHODS: The population of this cross-sectional study was 3310 medical doctors who graduated from Jichi Medical University from 1978 to 2012. The study instrument was a self-administered questionnaire that was mailed in August 2012 to investigate their age class, specialty, workplace, exercise habits, and practices of exercise counseling for CKD. RESULTS: 581 (64.8%) medical doctors practiced the management of CKD among a total of 933 responses. These 581 medical doctors were defined as CKD primary care physicians and their answers were analyzed. CKD primary care physicians' own exercise habits (frequencies and intensities) were as follows: frequencies: daily, 71 (12.1%); ≥ 2-3 times/week, 154 (26.5%); ≥ 1 time/week, 146 (25.1%); and ≤ 1 time/month, 176 (30.2%); intensities: high (≥ 6 Mets), 175 (30.1%); moderate (4-6 Mets), 132 (22.7%); mild (3-4 Mets), 188 (32.3%); very mild (<3 Mets), 47 (8.1%); and none, 37 (6.4%). The CKD primary care physicians' exercise recommendation levels for CKD patients were as follows: high, 31 (5.3%); moderate, 176 (29.7%); low, 256 (44.0%); and none, 92 (15.8%). The CKD primary care physicians' exercise recommendations for CKD patients were significantly related to their own exercise frequency (p < 0.001), but they were not related to their age, specialty, workplace, or exercise intensity. CONCLUSIONS: CKD primary care physicians' exercise recommendation level for CKD patients was limited. In addition, CKD primary care physicians' own exercise habits influenced the exercise counseling for CKD patients. The establishment of guidelines for exercise by CKD patients and their dissemination among primary care physicians are needed.(University Hospital Medical Information Network Clinical Trial Registry. number, UMIN000011803. Registration date, Sep/19/2013).

Relationship of Thyroid Function with Renal Hemodynamics and Cholesterol Metabolism in Proteinuric Kidney Disease: A Pilot Study.

Nephrotic syndrome and hypothyroidism are respectively reported to influence renal hemodynamics and hypercholesterolemia. However, the relationship of proteinuria-associated thyroid function with renal hemodynamics and cholesterol metabolism has yet to be determined in a simultaneous analysis of thyroid, renal, and cholesterol variables. We investigated the hypothesis that the changes in thyroid hormones by proteinuria may contribute to changes in cholesterol metabolism and renal hemodynamics by proteinuria. Twenty-nine patients (17 men and 12 women) with proteinuric kidney disease (mean age 46 years) were enrolled in a pilot study. Data for serum free triiodothyronine (FT3), free thyroxine (FT4), total cholesterol, and filtration fraction (FF; assessed by para-aminohippuric acid clearance) were used in variable-adjusted correlation analyses. The patients had the following data (mean ± standard deviation): urinary protein 5.18 ± 3.28 g/day, FT3 2.18 ± 0.44 pg/mL, FT4 1.03 ± 0.26 ng/dL, FF 0.27 ± 0.07, and total cholesterol 327 ± 127 mg/dL. There was a significant positive correlation of FT3 with FF (ß = 0.58, p = 0.01) and a significant inverse correlation of FT4 with total cholesterol (ß = -0.40, p = 0.01). A positive correlation of FT3 with FF and an inverse correlation of FT4 with total cholesterol were demonstrated in patients with proteinuric kidney disease. The proteinuria-associated reduction in serum thyroid hormone levels was correlated with hypercholesterolemia and the reduced glomerular FF. Further studies of these relationships are required.

Urinary Epidermal Growth Factor Level as a Noninvasive Indicator of Tubular Repair in Patients with Acute Kidney Injury.

Epidermal growth factor (EGF), an essential factor for the proliferation and survival of renal tubular cells, is expressed by distal tubules and normally excreted via urine. Previous studies in rats demonstrated that acute tubular injury reduces urinary EGF levels. However, it is unclear whether urinary EGF is a suitable monitoring marker of tubular repair status after acute kidney injury (AKI) in humans. To address this question, we measured serum and urinary EGF in patients with AKI (n = 99) using ELISA and investigated whether urinary EGF levels were associated with the severity of tubular injury and renal prognosis. Urinary EGF was abundant in healthy controls but showed a significant decrease in AKI patients (14,522 ± 2190 pg/mL vs. 3201 ± 459.7 pg/mL, p < 0.05). The urinary EGF level in patients with renal AKI was notably lower than that in patients with pre-renal AKI. Furthermore, the urinary EGF level in patients with AKI stage 3 was significantly lower than that in patients with AKI stage 1. Urinary EGF levels were negatively correlated with urinary ß-2MG and serum creatinine levels but positively correlated with hemoglobin levels and eGFR. Urinary EGF was not significantly correlated with urinary NAG, α-1MG, L-FABP, NGAL, KIM-1, or urinary protein concentrations. No significant correlation was observed between serum and urinary EGF levels, suggesting that urinary EGF is derived from the renal tubules rather than the blood. In living renal transplantation donors, the urinary EGF/Cr ratio was approximately half the preoperative urinary EGF/Cr ratio after unilateral nephrectomy. Collectively, these data suggest that urinary EGF is a suitable noninvasive indicator of not only the volume of functional normal renal tubules but also the status of tubular repair after AKI.

Potential Utility of Urinary Follistatin as a Non-Invasive Indicator of Acute Tubular Damage in Patients with Acute Kidney Injury.

Activin A is known to impede tubular repair following renal ischemia, whereas exogenous follistatin, an activin A antagonist, has been shown to ameliorate kidney damage in rats. Despite these findings, the precise role of endogenous follistatin in the kidney has yet to be elucidated. In this study, we investigated the localization of follistatin in the normal human kidney and its potential utility as a marker for acute kidney injury (AKI). In a total of 118 AKI patients and 16 healthy adults, follistatin levels in serum and urine were quantified using ELISA, and correlations with clinical parameters were analyzed. Follistatin-producing cells were positive for Na-Cl co-transporter and uromodulin, but negative for aquaporin 1 and aquaporin 2. Unlike healthy adults, urinary follistatin significantly increased in AKI patients, correlating positively with AKI severity. Urinary follistatin levels were notably higher in patients needing renal replacement therapy. Significant correlations were observed with urinary protein, α1 microglobulin, and urinary NGAL, but not with urinary KIM-1, urinary L-FABP, urinary NAG, urinary ß2 microglobulin, or serum creatinine. Interestingly, no correlation between urinary and serum follistatin levels was identified, indicating a renal origin for urinary follistatin. In conclusion, follistatin, produced by distal tubules, is detectable in the urine of AKI patients, suggesting its potential as a valuable marker for monitoring acute tubular damage severity in AKI.