Effects of sodium-glucose co-transporter 2 inhibitors on ultrafiltration in patients with peritoneal dialysis: a protocol for a randomized, double-blind, placebo-controlled, crossover trial (EMPOWERED).

BACKGROUND: Volume overload is common and associated with high mortality in patients on peritoneal dialysis (PD). Traditional strategies including diuretics, water/salt restriction, and icodextrin-based solutions cannot always fully correct this condition, necessitating novel alternative strategies. Recent studies confirmed the expression of sodium-glucose cotransporter 2 (SGLT2) in the human peritoneum. Experimental data suggest that SGLT2 inhibitors decrease glucose absorption from the PD solution, thereby increasing the ultrafiltration volume. This trial aims to assess whether SGLT2 inhibitors increase the ultrafiltration volume in patients on PD. METHODS: The EMPOWERED trial (trial registration: jRCTs051230081) is a multicenter, randomized, double-blind, placebo-controlled, crossover trial. Patients with clinically diagnosed chronic heart failure are eligible regardless of the presence of diabetes if they use at least 3 L/day glucose-based PD solutions. Participants will be randomly assigned (1:1) to receive empagliflozin 10 mg once daily and then placebo or vice versa. Each treatment period will last 8 weeks with a 4-week washout period. This study will recruit at least 36 randomized participants. The primary endpoint is the change in the daily ultrafiltration volume from baseline to week 8 in each intervention period. The key secondary endpoints include changes in the biomarkers of drained PD solutions, renal residual function, and anemia-related parameters. CONCLUSIONS: This trial aims to assess the benefit of SGLT2 inhibitors in fluid management with a novel mechanism of action in patients on PD. It will also provide insights into the effects of SGLT2 inhibitors on solute transport across the peritoneal membrane and residual renal function.

Conservative kidney management and kidney supportive care: core components of integrated care for people with kidney failure.

Integrated kidney care requires synergistic linkage between preventative care for people at risk for chronic kidney disease and health services providing care for people with kidney disease, ensuring holistic and coordinated care as people transition between acute and chronic kidney disease and the 3 modalities of kidney failure management: conservative kidney management, transplantation, and dialysis. People with kidney failure have many supportive care needs throughout their illness, regardless of treatment modality. Kidney supportive care is therefore a vital part of this integrated framework, but is nonexistent, poorly developed, and/or poorly integrated with kidney care in many settings, especially in low- and middle-income countries. To address this, the International Society of Nephrology has (i) coordinated the development of consensus definitions of conservative kidney management and kidney supportive care to promote international understanding and awareness of these active treatments; and (ii) identified key considerations for the development and expansion of conservative kidney management and kidney supportive care programs, especially in low resource settings, where access to kidney replacement therapy is restricted or not available. This article presents the definitions for conservative kidney management and kidney supportive care; describes their core components with some illustrative examples to highlight key points; and describes some of the additional considerations for delivering conservative kidney management and kidney supportive care in low resource settings.

The association between embedded catheter implantation and hospitalization costs for peritoneal dialysis initiation: a retrospective cohort study.

BACKGROUND: Compared with the conventional peritoneal dialysis (PD) catheter insertion, embedding PD catheter implantation is one of the procedures for planned PD initiation. However, facilities where embedded PD catheter implantation is available are limited, and the impact of embedded PD catheter implantation on hospitalization cost and length of hospitalization is unknown. METHODS: This retrospective single-center cohort study included 132 patients with PD initiation between 2005 and 2020. The patients were divided into two groups: 64 patients in the embedding group and 68 patients in the conventional insertion group. We created a multivariable generalized linear model (GLM) with the gamma family and log-link function to evaluate the association among catheter embedding, the duration and medical costs of hospitalization for PD initiation. We also evaluated the effect modification between age and catheter embedding. RESULTS: Catheter embedding (ß coefficient - 0.13 [95% confidence interval - 0.21, - 0.05]) and age (per 10 years 0.08 [0.03, 0.14]) were significantly associated with hospitalization costs. Catheter embedding (- 0.21 [- 0.32, - 0.10]) and age (0.11 [0.03, 0.19]) were also identified as factors significantly associated with length of hospitalization. The difference between the embedding group and the conventional insertion group in hospitalization costs for PD initiation (P for interaction = 0.060) and the length of hospitalization (P for interaction = 0.027) was larger in young-to-middle-aged patients than in elderly patients. CONCLUSIONS: Catheter embedding was associated with lower hospitalization cost and shorter length of hospitalization for PD initiation than conventional PD catheter insertion, especially in young-to-middle-aged patients.

Effect of improvement measures in reducing interruptions in a Japanese hospital pharmacy using a synthetic approach based on resilience engineering and systems thinking.

BACKGROUND: Workflow interruptions in pharmacies contribute to dispensing errors, a high-priority issue in patient safety, but have rarely been studied from a systemic perspective partly because of the limitations of the conventional reductionistic approach. This study aims to identify a mechanism for the occurrence of interruptions in a hospital pharmacy and find interventional points using a synthetic approach based on resilience engineering and systems thinking, and assess implemented measures for reducing them. METHODS: At a Japanese university hospital, we gathered information about performance adjustments of pharmacists in the inpatient medication dispensing unit for oral and topical medicines (IMDU-OT) and nurses in the inpatient wards (IPWs) in the medication dispensing and delivery process. Data about the workload and workforce of pharmacists were collected from hospital information systems. Telephone inquiries and counter services in the IMDU-OT, the primary sources of interruptions to pharmacists' work, were documented. The feedback structure between the IMDU-OT and the IPWs was analyzed using a causal loop diagram to identify interventional points. The numbers of telephone calls and counter services were measured cross-sectionally before (February 2017) and four months after implementing measures (July 2020). RESULTS: This study found that interruptions are a systemic problem emerging from the adaptive behavior of pharmacists and nurses to their work constraints, such as short staffing of pharmacists, which limited the frequency of medication deliveries to IPWs, and lack of information about the medication dispensing status for nurses. Measures for mitigating cross-system performance adjustments-a medication dispensing tracking system for nurses, request-based extra medication delivery, and pass boxes for earlier pick-up of medicines-were introduced. Following their implementation, the daily median number of telephone calls and counter services was significantly reduced (43 to 18 and 55 to 15, respectively), resulting in a 60% reduction in the total number of interruptions. CONCLUSION: This study found interruptions in the hospital pharmacy as a systemic problem that can be reduced by mitigating difficulties being compensated for by clinicians' cross-system performance adjustments. Our findings suggest that a synthetic approach can be effective for solving complex problems and have implications for methodological guidance for Safety-II in practice.

Time-dependent dysregulation of autophagy: Implications in aging and mitochondrial homeostasis in the kidney proximal tubule.

Autophagy plays an essential role in cellular homeostasis through the quality control of proteins and organelles. Although a time-dependent decline in autophagic activity is believed to be involved in the aging process, the issue remains controversial. We previously demonstrated that autophagy maintains proximal tubular cell homeostasis and protects against kidney injury. Here, we extend that study and examine how autophagy is involved in kidney aging. Unexpectedly, the basal autophagic activity was higher in the aged kidney than that in young kidney; short-term cessation of autophagy in tamoxifen-inducible proximal tubule-specific autophagy-deficient mice increased the accumulation of SQSTM1/p62- and ubiquitin-positive aggregates in the aged kidney. By contrast, autophagic flux in response to metabolic stress was blunted with aging, as demonstrated by the observation that transgenic mice expressing a green fluorescent protein (GFP)-microtubule-associated protein 1 light chain 3B fusion construct, showed a drastic increase of GFP-positive puncta in response to starvation in young mice compared to a slight increase observed in aged mice. Finally, proximal tubule-specific autophagy-deficient mice at 24 mo of age exhibited a significant deterioration in kidney function and fibrosis concomitant with mitochondrial dysfunction as well as mitochondrial DNA abnormalities and nuclear DNA damage, all of which are hallmark characteristics of cellular senescence. These results suggest that age-dependent high basal autophagy plays a crucial role in counteracting kidney aging through mitochondrial quality control. Furthermore, a reduced capacity for upregulation of autophagic flux in response to metabolic stress may be associated with age-related kidney diseases.

A pilot study of the effects of eplerenone add-on therapy in patients taking renin-angiotensin system blockers.

HYPOTHESIS: This study determined the parameters for predicting the clinical effects of eplerenone (Ep) add-on therapy on blood pressure (BP) and proteinuria in patients taking angiotensin-converting enzyme inhibitors (ACEis) or angiotensin II type I receptor blockers (ARBs). MATERIALS AND METHODS: Patients were treated with a gradual increase of Ep to a final dose of 50 mg/day for 2 months. In 35 patients, the efficacy of Ep was evaluated by peripheral BP, proteinuria, and the transtubular K gradient (TTKG). Fifteen patients had additional analysis for central BP, plasma renin activity (PRA) and plasma aldosterone concentration (PAC), measured in the supine position, and 24-hour urine collection before and after receiving Ep. RESULTS: Ep add-on therapy reduced the mean arterial pressure (p=0.0005) and central BP (p=0.009) independently to the baseline PAC. Ep induced PRA, but failed to show effects on PAC, TTKG, or albuminuria. Correlation analysis showed inverse relationships between the percent reduction in albuminuria and baseline PAC. CONCLUSIONS: Ep add-on therapy in patients taking renin-angiotensin system blockers is expected to reduce BP, even in patients with low PAC. In contrast, the anti-proteinuric action of Ep is dependent on baseline plasma aldosterone levels. TTKG is not appropriate for evaluating the efficacy of Ep.

Autophagic clearance of mitochondria in the kidney copes with metabolic acidosis.

Metabolic acidosis, a common complication of CKD, causes mitochondrial stress by undefined mechanisms. Selective autophagy of impaired mitochondria, called mitophagy, contributes toward maintaining cellular homeostasis in various settings. We hypothesized that mitophagy is involved in proximal tubular cell adaptations to chronic metabolic acidosis. In transgenic mice expressing green fluorescent protein-tagged microtubule-associated protein 1 light chain 3 (GFP-LC3), NH4Cl loading increased the number of GFP puncta exclusively in the proximal tubule. In vitro, culture in acidic medium produced similar results in proximal tubular cell lines stably expressing GFP-LC3 and facilitated the degradation of SQSTM1/p62 in wild-type cells, indicating enhanced autophagic flux. Upon acid loading, proximal tubule-specific autophagy-deficient (Atg5-deficient) mice displayed significantly reduced ammonium production and severe metabolic acidosis compared with wild-type mice. In vitro and in vivo, acid loading caused Atg5-deficient proximal tubular cells to exhibit reduced mitochondrial respiratory chain activity, reduced mitochondrial membrane potential, and fragmented morphology with marked swelling in mitochondria. GFP-LC3-tagged autophagosomes colocalized with ubiquitinated mitochondria in proximal tubular cells cultured in acidic medium, suggesting that metabolic acidosis induces mitophagy. Furthermore, restoration of Atg5-intact nuclei in Atg5-deficient proximal tubular cells increased mitochondrial membrane potential and ammoniagenesis. In conclusion, metabolic acidosis induces autophagy in proximal tubular cells, which is indispensable for maintaining proper mitochondrial functions including ammoniagenesis, and thus for adapted urinary acid excretion. Our results provide a rationale for the beneficial effect of alkali supplementation in CKD, a condition in which autophagy may be reduced, and suggest a new therapeutic option for acidosis by modulating autophagy.

Autophagy protects kidney proximal tubule epithelial cells from mitochondrial metabolic stress.

Chronic metabolic stress is related to diseases, whereas autophagy supplies nutrients by recycling the degradative products. Cyclosporin A (CsA), a frequently used immunosuppressant, induces metabolic stress via effects on mitochondrial respiration, and thereby, its chronic usage is often limited. Here we show that autophagy plays a protective role against CsA-induced metabolic stress in kidney proximal tubule epithelial cells. Autophagy deficiency leads to decreased mitochondrial membrane potential, which coincides with metabolic abnormalities as characterized by decreased levels of amino acids, increased tricarboxylic acid (TCA) ratio (the levels of intermediates of the latter part of the TCA cycle, over levels of intermediates in the earlier part), and decreased products of oxidative phosphorylation (ATP). In addition to the altered profile of amino acids, CsA decreased the hyperpolarization of mitochondria with the disturbance of mitochondrial energy metabolism in autophagy-competent cells, i.e., increased TCA ratio and worsening of the NAD(+)/NADH ratio, coupled with decreased energy status, which suggests that adaptation to CsA employs autophagy to supply electron donors from amino acids via intermediates of the latter part of the TCA cycle. The TCA ratio of autophagy-deficient cells was further worsened with decreased levels of amino acids in response to CsA, and, as a result, the deficiency of autophagy failed to adapt to the CsA-induced metabolic stress. Deterioration of the TCA ratio further worsened energy status. The CsA-induced metabolic stress also activated regulatory genes of metabolism and apoptotic signals, whose expressions were accelerated in autophagy-deficient cells. These data provide new perspectives on autophagy in conditions of chronic metabolic stress in disease.

Retention of fetuin-A in renal tubular lumen protects the kidney from nephrocalcinosis in rats.

The serum glycoprotein fetuin-A is an important inhibitor of extraosseous calcification. The importance of fetuin-A has been confirmed in fetuin-A null mice, which develop widespread extraosseous calcification including the kidney. However, the mechanism how fetuin-A protects kidneys from nephrocalcinosis remains uncertain. Here, we demonstrate that intratubular fetuin-A plays a role in the prevention of nephrocalcinosis in the proximal tubules. Although normal rat kidney did not express mRNA for fetuin-A, we found punctate immunohistochemical staining of fetuin-A mainly in the S1 segment of the proximal tubules. The staining pattern suggested that fetuin-A passed through the slit diaphragm, traveled in the proximal tubular lumen, and was introduced into proximal tubular cells by megalin-mediated endocytosis. To test this hypothesis, we inhibited the function of megalin by intravenous injection of histidine-tagged soluble receptor-associated protein (His-sRAP), a megalin inhibitor. His-sRAP injection diminished fetuin-A staining in the proximal tubules and led to urinary excretion of fetuin-A. We further analyzed the role of fetuin-A in nephrocalcinosis. Continuous injection of parathyroid hormone (PTH) 1-34 induced nephrocalcinosis mainly in the proximal tubules in rats. His-sRAP retained fetuin-A in renal tubular lumen and thereby protected the kidneys of PTH-treated rats from calcification. Our findings suggest that tubular luminal fetuin-A works as a natural inhibitor against calcification in the proximal tubules under PTH-loaded condition.

Prognostic significance of left ventricular hypertrophy observed at dialysis initiation depends on the pre-dialysis use of erythropoiesis-stimulating agents.

BACKGROUND: Recent experimental studies suggest that erythropoietin promotes beneficial myocardial remodeling during left ventricular hypertrophy (LVH); however, such compensatory capacity may be limited due to insufficient erythropoietin production in chronic kidney disease patients. Thus, this study aimed to explore the effect of pre-dialysis erythropoiesis-stimulating agent (ESA) use on the prognostic significance of LVH in dialyzed patients. METHODS: This retrospective study included 404 consecutive patients who started dialysis between 2001 and 2009. The interaction of ESA with the association between left ventricular mass index (LVMI) observed at dialysis initiation and all-cause and cardiovascular mortality was analyzed at the end of 2010 using the Cox model. RESULTS: During a median follow-up of 36.5 months, 164 patients died, 31 of them from heart failure. The frequency of pre-dialysis ESA use was 58.7 % and median LVMI was 160.3 g/m(2). Of interest, patients with the lowest tertile of LVMI had worse survival compared with those with each subsequent tertile. LVMI was inversely associated with all-cause mortality [hazard ratio (HR) 0.991, 95 % confidence interval (CI) 0.988-0.995, P = 0.000] after extensive adjustment including ejection fraction, whereas the prognostic value of LVMI for cardiovascular mortality was dependent on pre-dialysis ESA use [adjusted HR 1.010, 95 % CI 0.999-1.020, P = 0.065 for pre-dialysis ESA(+) and 0.978, 95 % CI 0.967-0.989, P = 0.000 for pre-dialysis ESA(-), respectively]. CONCLUSIONS: Our results suggest that reverse epidemiology may exist between LVH and mortality and that pre-dialysis ESA use may modify the prognostic significance of LVH observed at dialysis initiation for cardiovascular mortality in dialyzed patients.

Febuxostat suppressed renal ischemia-reperfusion injury via reduced oxidative stress.

Febuxostat is a novel selective inhibitor of xanthine oxidase (XO), approved for treating hyperuricemia. XO inhibits the generation of uric acid (UA) as well as the resulting generation of superoxide. During renal ischemia-reperfusion (I/R) injury, the burst of reactive oxygen species (ROS) can trigger the inflammation and the tubular cell injury. As XO is a critical source of ROS, inhibition of XO could be a therapeutic target for I/R injury. Therefore, we performed this study to test the therapeutic effect of febuxostat on renal I/R injury. Sprague-Dawley rats, received vehicle or febuxostat, were subjected to right nephrectomy and left renal I/R injury. Febuxostat significantly suppressed XO activity, and thereby reduced oxidative stress, assessed by nitrotyrosine, thiobarbituric acid-reactive substances (TBARS) and urine 8-isoprostane. Furthermore, febuxostat reduced the induction of endoplasmic reticulum (ER) stress, assessed by GRP-78, ATF4, and CHOP. Vehicle-treated I/R injured rats exhibited elevated serum creatinine and UN, which were significantly suppressed in febuxostat-treated I/R-injured rats. Histological analysis revealed that fubuxostat-treated rats showed less tubular injury and interstitial fibrosis with reduction in ED1-positive macrophage infiltration, TUNEL positive apoptotic tubular cells, and interstitial smooth muscle α actin (SMαA) expression, compared to vehicle-treated rats. In conclusion; novel XO inhibitor, febuxostat, can protect kidney from renal I/R injury, and may contribute to preserve kidney function.

A nonerythropoietic derivative of erythropoietin inhibits tubulointerstitial fibrosis in remnant kidney.

BACKGROUND: The tissue-protective effects of erythropoietin (EPO) have been extensively investigated, and EPO administration can raise the hemoglobin (Hb) concentration. Recently, we reported that carbamylated erythropoietin (CEPO) protected kidneys from ischemia-reperfusion injury as well as EPO. METHODS: To investigate the clinical applications of CEPO, we next evaluated the long-term therapeutic effect of CEPO using a tubulointerstitial model rat. We randomized remnant kidney model rats to receive saline, EPO, or CEPO for 8 weeks. RESULTS: CEPO- and EPO-treated rats had improved serum creatinine levels compared with saline-treated remnant kidney model rats, although the Hb level was significantly increased in EPO-treated rats. Two-photon microscopy revealed that EPO/CEPO significantly ameliorated tubular epithelial cell damage assessed by endocytosis. In addition, CEPO or EPO protected endothelial cells with a sustained blood flow rate. EPO or CEPO suppressed the number of TUNEL-positive apoptotic cells with weak αSMA staining. Furthermore, PCR analysis demonstrated that TGF-ß and type I collagen expression was attenuated in EPO- or CEPO-treated rats, accompanied by a significant decrease in interstitial fibrosis. CONCLUSION: We established a long-term therapeutic approach to protect tubulointerstitial injury with CEPO, and thus, the therapeutic value of this approach warrants further attention and preclinical studies.

Autophagy guards against cisplatin-induced acute kidney injury.

Autophagy is a highly conserved bulk protein degradation pathway involved in cellular homeostasis. Although emerging evidence indicates involvement of autophagy in various conditions, efforts to clarify the role of autophagy in renal tubules are beginning to be elucidated. In the present study, we examined the hypothesis that autophagy guards against acute kidney injury (AKI) by modulating several deteriorative pathways that lead to tubular cell death using a cisplatin-induced model of AKI. Cisplatin treatment of GFP-LC3 (green fluorescent protein-microtubule-associated protein 1 light chain 3) transgenic mice induced autophagy in kidney proximal tubules in a time-dependent manner. Proximal tubule-specific autophagy-deficient mice exhibited more severe cisplatin-induced AKI than did control mice, as assessed via kidney function and morphologic findings. In addition, cisplatin induced more severe DNA damage and p53 activation, concomitant with an increase in apoptotic cell number, and a massive accumulation of protein aggregates in autophagy-deficient proximal tubules. Cisplatin treatment significantly increased reactive oxygen species-producing damaged mitochondria in immortalized autophagy-deficient proximal tubular cells when compared with autophagy-retrieved control cells. In conclusion, autophagy guards kidney proximal tubules against AKI, possibly by alleviating DNA damage and reactive oxygen species production and by eliminating toxic protein aggregates. Enhancing autophagy may provide a novel therapeutic option to minimize AKI.

Towards developing new strategies to reduce the adverse side-effects of nonsteroidal anti-inflammatory drugs.

The antipyretic and analgesic actions of nonsteroidal anti-inflammatory drugs (NSAIDs) are caused by the inhibition of prostaglandin E(2) (PGE(2)), thromboxane A(2) and prostacyclin (PGI(2)) production. Accumulating evidence suggests that the inhibition of PGE(2) production can cause adverse side-effects of NSAIDs on fluid and blood pressure regulation, such as hypertension and edema formation. Since both cyclooxygenase (COX)-1 and COX-2 isoforms contribute to the production of PGE(2), selective COX-2 inhibitors are not free of these adverse side-effects although they may be less severe. Four subtypes of PGE(2) receptors have been identified. The antipyretic action of blunted PGE(2) production is mediated predominantly by a reduced input to the prostaglandin E receptor 3 (EP(3)) pathway, whereas the analgesic action is mediated predominantly by a reduced input to the EP(1) pathway and perhaps by contributions from the other EP receptors. Accordingly, some of the adverse side-effects might be moderated by combined use of NSAIDs with selective EP(2) or EP(4) agonists that do not block the antipyretic or analgesic actions of NSAIDs that are mediated by reduced activation of EP(1) or EP(3) receptors. Moreover, EP(2) receptor-deficient mice had salt-sensitive hypertension and EP(4) receptor blockade moderated salt and water excretion and both EP(2) and EP(4) agonists had renoprotective effects. This suggests that strategies to maintain activation of EP(2) and EP(4) receptors during NSAID administration may not only reduce adverse effects but might confer additional benefits. In conclusion, enhancing EP(2) and EP(4) receptor activity by administration of selective agonists during the administration of NSAIDs has the potential to permit treating fever, inflammation and pain but with marginal adverse effects on fluid or blood pressure regulation.

Gene polymorphisms contributing to hypertension in immunoglobulin A nephropathy.

BACKGROUND: Hypertension, which is affected by genetic and environmental factors, is one of the major risk factors for chronic kidney disease. Identification of the genetic factor contributing to hypertension in patients with chronic kidney disease may potentially refine a therapeutic strategy. METHODS: In the present multicenter cross-sectional study, 240 patients were eligible (aged 15-50 years with urinary protein ≥0.25 g/day) out of 429 patients who were diagnosed as having immunoglobulin (Ig) A nephropathy (IgAN) by renal biopsy between 1990 and 2005 and enrolled in our previous study, PREDICT-IgAN. The outcome was hypertension defined as ≥140 and/or ≥90 mmHg of systolic and diastolic blood pressure and/or use of antihypertensives at renal biopsy. We assessed associations between hypertension and 28 polymorphisms with the frequency of minor genotype ≥10% among 100 atherosclerosis-related polymorphisms using the Chi-squared test in dominant and recessive models. We identified polymorphisms associated with hypertension in multivariate logistic regression models. RESULTS: Baseline characteristics: hypertension 36.3%. Among 28 polymorphisms, the Chi-squared test revealed that CD14 (-159CC vs CT/TT, P = 0.03) and ACE (DD vs DI/II, P = 0.03) were significantly associated with hypertension after Bonferroni correction. Multivariate logistic regression models revealed that CD14 -159CC [vs CT/TT, odds ratio (OR) 3.58 (95% confidence interval (CI) 1.66-7.63)] and ACE DD [vs DI/II, OR 4.41 (95% CI 1.80-10.8), P = 0.001] were independently associated with hypertension. CONCLUSIONS: CD14 C-159T and ACE I/D contributed to hypertension in patients with IgAN.

Safety and efficacy of administering the maximal dose of candesartan in renal transplant recipients.

BACKGROUND: The regular dose of an angiotensin II type-1 receptor blocker (ARB) in renal transplant patients for hypertension is shown to be safe and effective; however, information on the appropriate dosing of ARBs in renal transplant patients is limited. We evaluate the efficacy and safety of the maximal dose of candesartan administered to renal transplant patients. METHODS: Sixty-nine recipients were enrolled in this study. Patients were divided into three groups based on the basal dose of candesartan: patients not taking candesartan (Group A); patients taking a low to medium dose of candesartan (2-4 mg/day; Group B); and patients taking a high dose of candesartan (8 mg/day; Group C). During the course of the study, the dose of candesartan was gradually increased to a final dose of 12 mg/day. Physiological and biochemical parameters were measured before and after the 12-month study period. RESULTS: Ninety-one percent of patients succeeded in continuing their administration of candesartan for 1 year and 75% tolerated the administration of the maximal dose of candesartan. Significant differences in proteinuria, albuminuria, serum creatinine, and estimated glomerular filtration rate (eGFR) level among the groups were detected. In Group A, candesartan reduced systolic blood pressure, decreased the levels of proteinuria, albuminuria, eGFR, and hemoglobin and increased plasma potassium, creatinine level, and plasma renin activity. CONCLUSION: The gradual increase of an ARB to its maximal dose in renal transplant patients is safe when carefully monitored. We were able to demonstrate the impact of maximal renin-angiotensin system (RAS) blockade on both proteinuria and albuminuria, which indicates the need for future, long-term randomized prospective trials to further establish the impact of maximal RAS blockade on renal and cardiovascular protection in transplant patients.

Effects of nicorandil on the reduction of BNP levels in patients with chronic kidney disease.

BACKGROUND: Patients with chronic kidney disease (CKD) still frequently experience cardiovascular events despite recent progress in treatment. We examined whether nicorandil, a hybrid nitrate and adenosine triphosphate-sensitive potassium channel opener, could improve a biomarker and physiological markers of cardiovascular events. METHODS: Patients with advanced stage CKD (stage III-V with or without peritoneal dialysis) were included in this trial if they were considered at high risk for cardiovascular events [past history of cardiovascular diseases, past history of coronary angiography, presence of endothelial dysfunction measured by reactive hyperemia peripheral arterial tonometry, and presence of high brain natriuretic peptide (BNP) values]. Patients were randomly assigned to be treated with or without oral nicorandil, 15 mg/day. BNP values and endothelial function (augmentation index, pulse wave velocity, and reactive hyperemia peripheral arterial tonometry) before and 1 month after the initiation of the trial were assessed. RESULTS: Nineteen patients (15 men, 4 women) with a mean age of 61 ± 10 (SD) years were included. The median baseline BNP value was 75.3 (interquartile range, 32.1-138.8) pg/ml, and the BNP level was significantly reduced in the nicorandil group (P < 0.05). Regression analysis demonstrated that only the use of nicorandil is related to a decrease of BNP levels [standardized ß coefficient, -75.1 (95% CI, -19.7 to -130.6), P = 0.01]. There were no significant changes in the rest of the parameters in the nicorandil group in comparison to the control group. The change in BNP levels was correlated with changes in the augmentation index (P < 0.01) and central pulse pressure (P = 0.03). CONCLUSIONS: Nicorandil treatment may reduce the level of BNP by reducing the central blood pressure in CKD patients.

Autophagy protects the proximal tubule from degeneration and acute ischemic injury.

Autophagy is a bulk protein degradation system that likely plays an important role in normal proximal tubule function and recovery from acute ischemic kidney injury. Using conditional Atg5 gene deletion to eliminate autophagy in the proximal tubule, we determined whether autophagy prevents accumulation of damaged proteins and organelles with aging and ischemic renal injury. Autophagy-deficient cells accumulated deformed mitochondria and cytoplasmic inclusions, leading to cellular hypertrophy and eventual degeneration not observed in wildtype controls. In autophagy-deficient mice, I/R injury increased proximal tubule cell apoptosis with accumulation of p62 and ubiquitin positive cytoplasmic inclusions. Compared with control animals, autophagy-deficient mice exhibited significantly greater elevations in serum urea nitrogen and creatinine. These data suggest that autophagy maintains proximal tubule cell homeostasis and protects against ischemic injury. Enhancing autophagy may provide a novel therapeutic approach to minimize acute kidney injury and slow CKD progression.

CD28 superagonist-induced regulatory T cell expansion ameliorates mesangioproliferative glomerulonephritis in rats.

BACKGROUND: Naturally occurring regulatory T cells (Treg) are essential for the prevention of autoimmunity and overshooting immune responses to pathogens; however, the involvement of Treg in mesangioproliferative glomerulonephritis, a major cause of chronic kidney disease, remains unclear. Superagonistic CD28-specific monoclonal antibodies (CD28SA) are highly effective activators of Treg in rats. METHOD: To confirm our hypothesis that CD28SA reduces the severity of experimental glomerulonephritis, anti-Thy1 nephritis model rats were treated with CD28SA or saline. RESULTS: CD28SA significantly suppressed the increase in proteinuria and serum creatinine levels. CD28SA-treated nephritic rats exhibited an increase in the infiltration of Treg in the glomeruli accompanied by infiltration of CD163-positive macrophages ("alternatively activated" macrophages). In addition, CD28SA significantly induced interleukin-10 mRNA expression in glomeruli, thereby ameliorating mesangial cell proliferation and extracellular matrix expansion. CONCLUSION: We established a new therapeutic approach to suppressing progressive glomerulonephritis. The therapeutic value of this approach warrants further attention and preclinical studies.