Search

Background: It is well known that kidney injury is vital organ damage in Fabry disease (FD). Renin–angiotensin system (RAS) inhibitors are known to reduce proteinuria in patients with chronic kidney disease (CKD) by dilating the glomerular export arteries and reducing intraglomerular pressure. This improvement in intraglomerular pressure, although lowering the glomerular filtration rate, is thought to prevent renal damage and be renoprotective in the long term. RAS inhibitors may be effective in FD patients with proteinuria to prevent the progression of kidney disease, however, the degree to which they are used in clinical practice is unknown. Methods: The J-CKD-DB-Ex is a comprehensive multicenter database that automatically extracts medical data on CKD patients. J-CKD-DB-Ex contains data on 187,398 patients in five medical centers. FD patients were identified by ICD-10. Clinical data and prescriptions of FD patients between January 1 of 2014, and December 31 of 2020 were used for the analysis. Results: We identified 39 patients with FD from the J-CKD-DB-Ex including those with suspected FD. We confirmed 22 patients as FD. Half of the patients received RAS inhibitors. RAS inhibitors tended to be used in CKD patients with more severe renal impairment. Conclusions: This case series revealed the actual clinical practice of FD patients with CKD. In particular, we found cases in which patients had proteinuria, but were not treated with RAS inhibitors. The database was shown to be useful in assessing the clinical patterns of patients with rare diseases. [ABSTRACT FROM AUTHOR]

Background: Chronic kidney disease (CKD) poses a significant health risk in contemporary society. Current CKD treatments primarily involve renin-angiotensin-aldosterone system inhibitors and mineralocorticoid receptor antagonists, albeit associated with hyperkalemia risks. A novel selective mineralocorticoid receptor antagonist, finerenone, offers a promising, safer alternative for CKD therapy. Summary: This review comprehensively assesses the role and efficacy of finerenone in CKD treatment by analyzing clinical and animal studies. Emerging evidence consistently supports finerenone's ability to effectively slow the progression of CKD. By targeting the mineralocorticoid receptor, finerenone not only mitigates renal damage but also exhibits a favorable safety profile, minimizing hyperkalemia concerns. Conclusion: Finerenone emerges as a valuable addition to CKD therapy, demonstrating potential benefits in delaying CKD progression while minimizing side effects. Nevertheless, further clinical trials are necessary to provide a comprehensive understanding of its safety and efficacy. [ABSTRACT FROM AUTHOR]

Background: MYH9-related disease (MYH9-RD) is characterized by congenital macrothrombocytopenia, Döhle body-like granulocyte inclusions, and nephropathy, which may progress to end-stage kidney disease (ESKD). However, information on the effects of renin-angiotensin system (RAS) inhibitors on kidney survival is currently lacking and the outcomes of kidney replacement therapy (KRT) in MYH9-RD are largely unknown. Methods: We conducted a cross-sectional nationwide survey by sending questionnaires to 145 institutions in Japan and analyzed data for 49 patients. Results: The median patient age was 27 years. Genetic analysis was performed in 37 (76%) patients. Twenty-four patients (65%) had MYH9 variants affecting the motor domain of non-muscle myosin heavy chain-IIA, and these patients had poorer kidney survival than those with variants affecting the tail domain (P = 0.02). There was no significant difference in kidney survival between patients treated with and without RAS inhibitors. Hemodialysis and peritoneal dialysis were performed in 16 and 7 patients, respectively. There were no major bleeding complications during the perioperative period or during follow-up, except for one patient. Most of the 11 patients who underwent kidney transplantation required perioperative red cell concentrate transfusions, but there was no graft loss during the median posttransplant observational period of 2.0 (interquartile range, 1.3–6.8) years. Conclusion: Our study demonstrated no beneficial effect of RAS inhibitors on kidney function in patients with MYH9-RD, indicating the need for further studies with more patients. All modalities of KRT are feasible options for MYH9-RD patients who progress to ESKD, with adequate attention to bleeding complications. [ABSTRACT FROM AUTHOR]

Background: In 2020, the Committee of Clinical Practical Guideline for IgA Nephropathy (IgAN) revised the clinical practice guidelines. Herein, we conducted a questionnaire survey to assess the potential discrepancies between clinical practice guidelines and real-world practice in Japan. Methods: A web-based survey of members of the Japanese Society of Nephrology was conducted between November 15 and December 28, 2021. Results: A total of 217 members (internal physicians: 203, pediatricians: 14) responded to the questionnaire. Of these respondents, 94.0% answered that the clinical practice guidelines were referred to "always" or "often." Approximately 66.4% respondents answered that histological grade (H-Grade) derived from the "Clinical Guidelines for IgA nephropathy in Japan, 3rd version" and the "Oxford classification" were used for pathological classification. Moreover, 73.7% respondents answered that the risk grade (R-grade) derived from the "Clinical Guidelines for IgA nephropathy in Japan, 3rd version" was referred to for risk stratification. The prescription rate of renin–angiotensin system blockers increased based on urinary protein levels (> 1.0 g/day: 88.6%, 0.5–1.0 g/day: 71.0%, < 0.5 g/day: 25.0%). Similarly, the prescription rate of corticosteroids increased according to proteinuria levels (> 1.0 g/day: 77.8%, 0.5–1.0 g/day: 52.8%, < 0.5 g/day: 11.9%). The respondents emphasized on hematuria when using corticosteroids. In cases of hematuria, the indication rate for corticosteroids was higher than in those without hematuria, even if the urinary protein level was 1 g/gCr or less. Few severe infectious diseases or serious deterioration in glycemic control were reported during corticosteroid use. Conclusion: Our questionnaire survey revealed real-world aspects of IgAN treatment in Japan. [ABSTRACT FROM AUTHOR]

Background: Alport syndrome is one of the most common inherited kidney diseases worldwide. A genetic test or kidney biopsy is necessary for a definite diagnosis of this disease, and an accurate diagnosis system for this disease is highly desired in each country. However, the current situation in Asian countries is not clear. Therefore, the tubular and inherited disease working group of the Asian Pediatric Nephrology Association (AsPNA) aimed to assess the current situation of diagnosis and treatment for Alport syndrome in Asia. Methods: The group conducted an online survey among the members of AsPNA in 2021–2022. Collected data included the number of patients for each inheritance mode, availability of gene tests or kidney biopsy, and treatment strategies for Alport syndrome. Results: A total of 165 pediatric nephrologists from 22 countries in Asia participated. Gene test was available in 129 institutes (78%), but the cost was still expensive in most countries. Kidney biopsy was available in 87 institutes (53%); however, only 70 can access electron microscopy, and 42 can conduct type IV collagen α5 chain staining. Regarding treatment, 140 centers use renin-angiotensin system (RAS) inhibitors (85%) for Alport syndrome patients. Conclusions: This study result might suggest that the system is underdeveloped enough to diagnose all Alport syndrome patients in most Asian countries. However, once diagnosed with Alport syndrome, most of them were treated with RAS inhibitors. These survey results can be used to address knowledge, diagnostic system, and treatment strategy gaps and improve the Alport patients' outcomes in Asian countries. [ABSTRACT FROM AUTHOR]

Background: Astragalus root is a commonly used herb in traditional Chinese medicine. Although renoprotective effects have been reported in some clinical and experimental studies, the details remain unknown. Methods: We used 5/6 nephrectomized rats as chronic kidney disease (CKD) models. At 10 weeks, they were divided into four groups, namely, CKD, low-dose astragalus (AR400), high-dose astragalus (AR800), and sham groups. At 14 weeks, they were sacrificed for the evaluation of blood, urine, mRNA expression in the kidney, and renal histopathology. Results: Kidney dysfunction was significantly improved following astragalus administration (creatinine clearance: sham group; 3.8 ± 0.3 mL/min, CKD group; 1.5 ± 0.1 mL/min, AR400 group; 2.5 ± 0.3 mL/min, AR800 group; 2.7 ± 0.1 mL/min). Blood pressure, urinary albumin, and urinary NGAL levels were significantly lower in the astragalus-treated groups than those in the CKD group. Excretion of urinary 8-OHdG, an oxidative stress marker, and intrarenal oxidative stress were lower in the astragalus-treated groups than those in the CKD group. Furthermore, the mRNA expression of NADPH p22 phox, NADPH p47 phox, Nox4, renin, angiotensin II type 1 receptor, and angiotensinogen in the kidney was lower in the astragalus-treated groups compared with the CKD group. Conclusion: This study suggests that astragalus root slowed CKD progression, possibly through the suppression of oxidative stress and the renin–angiotensin system. [ABSTRACT FROM AUTHOR]

Background: Evidence on renin–angiotensin system inhibitors (RASis) effect in reducing urinary protein levels in patients with nephrotic syndrome is insufficient. We determined whether RASis can induce complete remission (CR) in patients on immunosuppressive therapy. Methods: This cohort study included 84 adults (median age, 65 years; males, 57%) with primary nephrotic syndrome (excluding minimal change disease) not receiving RASis during enrollment in the Japanese Nephrotic Syndrome Cohort Study from January 2009 to December 2010, and were followed up for 5 years. Exposure and outcome were RASi initiation and first CR, respectively. Marginal structural models and Poisson regression were used to account for time-varying covariates and estimate causal effects of RASis on CR. Results: Overall, 51 (61%), 73 (87%), and 55 (66%) patients had membranous nephropathy, were prescribed immunosuppressive agents at baseline (1-month post-renal biopsy and/or at start of immunosuppressive therapy), and were prescribed RASis during the study period, respectively. Sixty-five patients experienced first CR (incidence rate, 5.05/100 person-months). RASi use was associated with a higher (adjusted incidence rate ratio [aIRR] 2.27, 95% confidence interval [CI] 1.06–4.84), and lower (aIRR: 0.17, 95% CI 0.04–0.68) first CR in patients with membranous nephropathy and other pathologies, respectively. Conclusion: RASis are beneficial as adjuvant therapy for inducing remission in patients with membranous nephropathy. [ABSTRACT FROM AUTHOR]

Background: Patients with immunoglobulin A nephropathy who present with focal mesangial proliferation (focal IgAN) can have a relatively good prognosis, and renin–angiotensin system inhibitor (RAS-i) is commonly used as the initial treatment. However, there are some complicated focal IgAN cases with resistance to RAS-i treatment or nephrotic-range proteinuria. Thus, combination therapy including corticosteroids is often used. This study aimed to evaluate the efficacy of combination therapy for complicated focal IgAN cases by comparing to diffuse mesangial proliferation (diffuse IgAN). Methods: We conducted a multicenter retrospective study on 88 children who received 2-year combination therapy. The participants were classified based on pathological severity: focal IgAN (n = 26) and diffuse IgAN (n = 62). Results: In total, 26 patients with focal IgAN and 52 with diffuse IgAN achieved proteinuria disappearance within 2 years (100 vs. 83.9%, P = 0.03). Moreover, the time to proteinuria disappearance was significantly shorter in the focal IgAN group than in the diffuse IgAN group (2.9 vs. 4.2 months, P < 0.01) and all patients with focal IgAN achieved proteinuria disappearance within 8 months. At the last observation (8.6 vs. 10.4 years, P = 0.13), only patients with diffuse IgAN (n = 12) had greater than stage 2 chronic kidney disease. In terms of irreversible adverse events, one patient exhibited cataracts. Conclusion: Combination therapy was significantly effective in patients with complicated focal IgAN. Moreover, the long-term prognosis was good, and the duration of combination therapy for complicated focal IgAN can be decreased to reduce adverse events. [ABSTRACT FROM AUTHOR]

Background: Chronic kidney disease (CKD) is involved in a progressive deterioration in renal function over the years and is now a global public health problem. Currently, reducing the number of patients progressing to end-stage renal failure is urgently necessary. Hypertension and CKD interact with each other, and good control of blood pressure (BP) can improve CKD patients' prognosis. With the current global trend for more strict BP control, the importance of BP management and the need for medication to achieve this strict goal are increasing. Calcium channel blockers (CCBs), which target voltage-dependent calcium channels, are frequently used in combination with renin–angiotensin–aldosterone system inhibitors for CKD patients because of their strong BP-lowering properties and relatively few adverse side effects. Calcium channels have several subtypes, including L, N, T, P/Q, and R, and three types of CCBs, L-type CCBs, L-/T-type CCBs, and L-/N-type CCBs, that are available. Nowadays, the new functions and effects of the CCBs are being elucidated. Conclusion: We should use different types of CCBs properly depending on their pharmacological effects, such as the strength of antihypertensive effects and the organ protection effects, taking into account the pathophysiology of the patients. In this article, the role and the use of CCBs in CKD patients are reviewed. [ABSTRACT FROM AUTHOR]

Background: Esaxerenone has potential renoprotective effects and reduces the urinary albumin-to-creatinine ratio (UACR) in patients with diabetic kidney disease and overt nephropathy. We investigated the efficacy and safety of esaxerenone in Japanese patients with type 2 diabetes (T2D) and macroalbuminuria (UACR ≥ 300 mg/g creatinine). Methods: We conducted a multicenter, single-arm, open-label phase III study in 56 patients with T2D and UACR ≥ 300 mg/g creatinine with estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 and treated with a renin–angiotensin system inhibitor. Patients received esaxerenone for 28 weeks at 1.25 mg/day initially with titration to 2.5 mg/day based on serum potassium (K+) monitoring. Efficacy was evaluated as the change in UACR from baseline to week 28. Safety endpoints included adverse events (AEs), incidence of serum K+ increase, and change in eGFR from baseline. Results: UACR decreased by 54.6% (95% CI 46.9%, 61.3%) on average from baseline (544.1 mg/g creatinine) to the end of treatment (246.8 mg/g creatinine); 51.8% of patients showed improvement to early nephropathy. AE incidence was 69.6%. Three patients (5.4%) had serum K+ levels ≥ 6.0 mEq/L or ≥ 5.5 mEq/L on two consecutive occasions. Hyperkalemia in two patients was transient and resolved during the treatment period. One patient discontinued following two consecutive serum K+ values ≥ 5.5 mEq/L. The maximum change from baseline in eGFR was − 8.3 mL/min/1.73 m2 at week 24. Conclusions: Esaxerenone reduced UACR in Japanese patients with T2D and UACR ≥ 300 mg/g creatinine; more than half experienced a transition from UACR ≥ 300 mg/g creatinine to UACR < 300 mg/g creatinine. Clinical trial registration: JapicCTI-173696 [ABSTRACT FROM AUTHOR]

Background: In 2019, a nationwide questionnaire survey on the management of chronic kidney disease (CKD) was circulated to general practitioners (GPs) throughout Japan by The Japan Physicians Association. The aim was to assess the current state of CKD medical care in the country and evaluate the utilization of CKD-specific guidelines in the treatment by GPs. Methods: The voluntary survey targeted all members of Japan Physicians Association, a nationwide organization consisting primarily of 15,000 GPs in clinics throughout the country. GPs were divided into groups: 171 GPs using and 414 GPs not using the guidelines. Comparisons between the groups' responses were made using propensity score matching and component cluster analysis. Results: Overall responses revealed that the estimated glomerular filtration rate's utilization rate was high (95.1%). However, evidence-practice gaps in urine protein quantification and anemia remedy were prominent. There were significantly favorable answers in terms of CKD management in the user group compared with those in the non-user group, except for the questions about a urine check at the first visit, stopping the use of renin-angiotensin system inhibitors, and the target blood pressure for elderly CKD patients. The differences suggest that utilization of the CKD guidelines has improved CKD management practices by GPs. Conclusions: Further promotion of CKD guidelines utilization (28% in this survey) is considered valid for CKD medical education. [ABSTRACT FROM AUTHOR]

Background: Hyperkalemia is associated with many chronic diseases and renin-angiotensin-aldosterone system inhibitor therapy. Sodium zirconium cyclosilicate (SZC), an oral, highly selective cation-exchanger, is approved for the treatment of hyperkalemia. Methods: This phase 3, multicenter, open-label, single-arm, flexible-dose study assessed the safety and efficacy of SZC in Japanese patients with hyperkalemia during a correction phase of up to 3 days and long-term (1 year) maintenance phase (NCT03172702). Results: Overall, 150 patients received treatment during both study phases; the study population was generally representative of hyperkalemic Japanese patients in clinical practice. Most patients (78.7%) had three doses of SZC during the correction phase. All but one patient received SZC for ≤ 48 h before transitioning to the maintenance phase. In the maintenance phase, mean (standard deviation; SD) exposure to the study drug was 319.4 (98.1) days and mean (SD) dose was 7.38 (2.85) g/day. Adverse events (AEs) were reported in 131 patients (87.3%); most were mild. The most common treatment-related AEs as evaluated by investigators were constipation (6.7%), peripheral edema (4.0%), and hypertension (2.7%). In the correction phase, 78.7% of patients were normokalemic at 24 h and 98.7% within 48 h; ≥ 65.5% maintained normokalemia throughout the maintenance phase. Conclusion: After a year of exposure, SZC treatment was well tolerated by Japanese patients and potassium levels were well controlled. [ABSTRACT FROM AUTHOR]

Excessive activation of the tissue renin–angiotensin system through angiotensin II (Ang II) type 1 receptor (AT1R) plays a pivotal role in the pathogenesis of hypertension and related organ injury. AT1R-associated protein (ATRAP/Agtrap) was identified as a molecule specifically interacting with the carboxyl- terminal domain of AT1R. The results of in vitro studies showed that ATRAP suppresses Ang II-mediated pathological responses in cardiovascular cells by promoting AT1R internalization. With respect to the tissue distribution and regulation of ATRAP expression in vivo, ATRAP is broadly expressed in many tissues as is AT1R including kidney. The results of in vivo study employing genetic engineered mice with modified ATRAP expression showed that ATRAP inhibits cardiovascular injuries provoked by Ang II-induced hypertension, along with preserving physiological AT1R signaling. In addition, we have shown that ATRAP functions as an endogenous modulator so as to prevent hypertension in response to pathological stimuli, by regulating renal sodium handling. Furthermore, ATRAP may have an AT1R-independent function of renal proximal tubule to protect aging and fibrosis. These results suggest the clinical potential benefit of an ATRAP activation strategy in the treatment of hypertension and cardiorenal and vascular diseases. [ABSTRACT FROM AUTHOR]

Background: Renin–angiotensin system blockers (RASBs) reduce end-stage kidney disease and cardiovascular event (CVE) development in chronic kidney disease. However, whether RASBs improve long-term prognosis in kidney transplant (KT) recipients remain unknown. Method: We investigated 900 kidney transplant patients in a multicenter retrospective cohort study in Japan and compared death-censored graft survival and CVE (total, cardiac events, stroke) based on RASB use within 12 months after KT. The associations were examined using a Cox hazard model and propensity score-matching analysis. Results: The cohort comprised 375 patients treated with RASBs (RASB group) and 525 patients without RASBs (control group). The median observational period was 82 months, with 68 patients reaching graft loss: 79 total CVE, 36 cardiac events, 26 stroke. In a matching cohort comprising 582 patients, death-censored graft survival, total CVE, and cardiac events were not different between the two groups. Only stroke incidence rate was significantly lower in the RASB group compared with the control group (1.4 vs. 6.4 per 1000 patients/year, log-ranked P = 0.005). In a multivariable analysis, stroke events were also significantly lower in the RASB group compared with the control group (Hazard ratio and 95% confidence interval, 0.20 [0.04–0.62]). Conclusion: Thus, RASBs potentially reduce stroke events in KT recipients. [ABSTRACT FROM AUTHOR]

Background: A higher heart rate is one of the risk factors for heart failure and cardiovascular disease. Activation of the intrarenal renin–angiotensin system (RAS) plays an important role in the development of hypertension and renal damage. However, the association between heart rate and intrarenal RAS activation is unclear. Methods: We investigated the relationship between heart rate and urinary angiotensinogen (U-AGT) excretion, a surrogate marker for intrarenal RAS activity, in ten subjects without chronic kidney disease (CKD) and 72 CKD patients who were not taking medications that influence heart rate and RAS blockers (age 50.0 ± 17.4 years, 27 men and 45 women, serum creatinine (sCr) 1.85 ± 2.71 mg/dL, blood pressure 120.5 ± 15.8/72.9 ± 10.1 mmHg, heart rate 67.3 ± 8.9 /min, urinary protein excretion 1.27 ± 2.63 g/day, and U-AGT excretion 747.4 ± 2714.6 µg/day). Results: As heart rate is influenced by behavior and emotion, we divided it into daytime and nighttime. Heart rate had a significant positive association with sCr levels during daytime and nighttime in CKD patients but not in non-CKD subjects. Moreover, although heart rate was not associated with U-AGT excretion levels in non-CKD subjects, it was associated with U-AGT excretion levels during daytime (r = 0.23 and p = 0.047) and nighttime (r = 0.45 and p < 0.01) in CKD patients. Multiple linear regression analysis revealed that heart rate had a significant positive association with the U-AGT excretion levels during nighttime, but not daytime, after adjustments for age, sex, body mass index, and sCr (β = 0.31 and p = 0.034). Conclusion: Heart rate is associated with U-AGT excretion levels, especially during the nighttime, in CKD patients. [ABSTRACT FROM AUTHOR]

Background: Global sclerosis has been reported as the risk factor of IgAN. In Oxford classification, global sclerosis was correlated with tubulointerstitial (T) lesions. Therefore, in patients with T lesions, renin–angiotensin system inhibitors (RASI) might be effective by decreasing glomerular hyperfiltration and hypertension. However, these beneficial effects of RASI have not been reported. Methods: In this retrospective cohort study, we divided 87 IgAN patients with T1/2 lesions into two groups: RASI group (n = 47, treated with RASI) and APA group (n = 40, treated with anti-platelet agents). We analyzed the background of each group, the serial changes of blood pressure and the amount of proteinuria (U-Prot), progression to end-stage renal disease, and the risk factors for progression. Results: After propensity score matching, 22 cases from each group were selected, and clinical and histological characteristics were similar. Serial changes of blood pressure had been significantly decreased in RASI group (p = 0.0029), but not in the APA group. Proteinuria was tended to decrease in RASI group, though it was not significant (1.14–0.47 g/gCre) and it was similar in APA group (0.95–0.85 g/gCre). 20 year renal survival rate was 59.5% in RASI group, whereas 21.3% in APA group (p = 0.0119). In multivariate Cox regression analysis, RASI was an independent factor to prevent from progression to ESRD (HR 5.91, p = 0.0039). Conclusion: RASI has shown a significant beneficial effect on histologically advanced IgAN patients with T lesions. These results are compatible with the previous studies that reported the beneficial effects of RASI on clinically advanced IgAN patients. [ABSTRACT FROM AUTHOR]

Background: Renal resistive index (RI) calculated using renal Doppler ultrasonography (RDU) has recently been considered a clinically important indicator of renal outcome, survival, and systemic arteriosclerotic disorders. However, the cause of RI elevation remains unclear. The present study was an effort to first, identify the factors related to RI elevation, and second, understand the effect of renin-angiotensin system inhibitors (RAS-Is) on renal RI elevation. Methods: We carried out this single-center case-control study among 100 CKD patients, recruited from outpatients who underwent RDU more than twice, at least a year apart. The rate of renal RI change per year (dRIpy) was chosen as the dependent variable: [(last examined renal RI—initial examined renal RI)/(initial examined renal RI × period of observation) × 100 (%/year)]. We examined the association between dRIpy and other clinical and biological data. Results: Among 100 CKD patients, the average serum creatinine and eGFR were 1.76 ± 0.84 mg/dL and 37.0 ± 18.2 ml/min/1.73 m2, respectively. The average dRIpy in all patients was 1.8 ± 1.4%/year. The linear multiple regression demonstrated that dRIpy was positively associated with the presence of diabetes mellitus (DM) and high low-density lipoprotein cholesterol (LDL) levels, and negatively with eGFR and RAS-I use. Conclusions: This study demonstrated that the elevation of RI was related to DM, eGFR, high LDL, and the use of RAS-Is. In particular, RAS-Is could contribute towards suppressing the elevation of RI in CKD patients and towards preventing the development of renal failure in CKD patients. [ABSTRACT FROM AUTHOR]

Background: We recently demonstrated that preterm neonates have higher urinary angiotensinogen (AGT) levels than full-term neonates. Here, we tested the hypothesis that enhanced neonatal AGT expression is associated with intrarenal renin–angiotensin system (RAS) status during kidney development. Methods: We prospectively recruited neonates born at our hospital and healthy children with minor glomerular abnormalities between April 2013 and March 2017. We measured neonatal plasma and urinary AGT levels at birth and 1 year later and assessed renal AGT expression in kidney tissues from neonates and healthy children using immunohistochemical (IHC) analysis. Results: Fifty-four neonates and eight children were enrolled. Although there were no changes in plasma AGT levels, urinary AGT levels were significantly decreased 1 year after birth. Urinary AGT levels at birth were inversely correlated with gestational age, and urinary AGT levels at birth and 1 year later were inversely correlated with estimated glomerular filtration rate 1 year after birth. IHC analysis showed that renal AGT expression in neonates was higher than that in healthy children and inversely correlated with gestational age. Conclusions: Enhanced AGT expression and urinary AGT excretion may reflect intrarenal RAS activation associated with kidney development in utero. [ABSTRACT FROM AUTHOR]

Renin-angiotensin-aldosterone system (RAAS) plays important roles in regulating renal hemodynamics and functions, as well as in the pathophysiology of hypertension and renal disease. In the kidney, angiotensin II (Ang II) production is controlled by independent multiple mechanisms. Ang II is compartmentalized in the renal interstitial fluid with much higher concentrations than those existing in the circulation. Inappropriate activation of the intrarenal RAAS is an important contributor to the pathogenesis of hypertension and renal injury. It has been revealed that intrarenal Ang II levels are predominantly regulated by angiotensinogen and therefore, urinary angiotensinogen could be a biomarker for intrarenal Ang II generation. In addition, recent studies have demonstrated that aldosterone contributes to the progression of renal injury via direct actions on glomerular podocytes, mesangial cells, proximal tubular cells and tubulo-interstitial fibroblasts through the activation of locally expressed mineralocorticoid receptor. Thus, it now appears that intrarenal RAAS is independently regulated and its inappropriate activation contributes to the pathogenesis of the development of hypertension and renal disease. This short review article will focus on the independent regulation of the intrarenal RAAS with an emphasis on the specific role of angiotensinogen. [ABSTRACT FROM AUTHOR]

Background: Activation of the intrarenal renin-angiotensin system (RAS) plays a critical role in the pathophysiology of chronic kidney disease (CKD) and hypertension. It has been reported that reactive oxygen species (ROS) are important components of intrarenal RAS activation. Melatonin is recognized as a powerful antioxidant, and we recently reported that impaired nighttime melatonin secretion correlates negatively with urinary angiotensinogen excretion, the surrogate marker of intrarenal RAS activity in patients with CKD. However, whether melatonin supplementation ameliorates the augmentation of intrarenal RAS in CKD has remained unknown. We aimed to clarify whether exogenous melatonin ameliorates intrarenal RAS activation via the reduction of ROS production.Methods: 5/6 Nephrectomized (Nx) rats were used as a chronic progressive CKD model and compared with sham-operated control rats. The Nx rats were divided into untreated Nx rats and melatonin-treated Nx rats. The levels of intrarenal RAS, ROS components, and renal injury were evaluated after 4 weeks of treatment.Results: Compared with the control rats, the untreated Nx rats exhibited significant increases in intrarenal angiotensinogen, angiotensin II (AngII) type 1 receptors, and AngII, accompanied by elevated blood pressure, higher oxidative stress (8-hydroxy-2′-deoxyguanosine), lower antioxidant (superoxide dismutase) activity, and increased markers of interstitial fibrosis (α-smooth muscle actin, Snail, and type I collagen) in the remnant kidneys. Treatment with melatonin significantly reversed these abnormalities.Conclusion: Antioxidant treatment with melatonin was shown to ameliorate intrarenal RAS activation and renal injury in a 5/6 Nx rat model. [ABSTRACT FROM AUTHOR]

Background: Activation of the intrarenal renin-angiotensin system (RAS) plays a critical role in the pathophysiology of chronic kidney disease (CKD) and hypertension. The circadian rhythm of intrarenal RAS activation leads to renal damage and hypertension, which are associated with diurnal blood pressure (BP) variation. The activation of intrarenal RAS following reactive oxygen species (ROS) activation, sympathetic hyperactivity and nitric oxide (NO) inhibition leads to the development of renal damage. Melatonin is a hormone regulating the circadian rhythm, and has multiple functions such as anti-oxidant and anti-adrenergic effects and enhancement of NO bioavailability. Nocturnal melatonin concentrations are lower in CKD patients. However, it is not known if impaired endogenous melatonin secretion is related to BP, intrarenal RAS, or renal damage in CKD patients. Methods: We recruited 53 CKD patients and conducted 24-h ambulatory BP monitoring. urine was collected during the daytime and nighttime. We investigated the relationship among the melatonin metabolite urinary 6-sulphatoxymelatonin (U-aMT6s), BP, renal function, urinary angiotensinogen (U-AGT), and urinary albumin (U-Alb). Results: Patients' U-aMT6s levels were significantly and negatively correlated with clinical parameters such as renal function, systolic BP, U-AGT, and U-Alb, during both day and night. Multiple regression analyses for U-aMT6s levels were performed using age, gender, renal function, and each parameter (BPs, U-AGT or U-Alb), at daytime and nighttime. U-aMT6s levels were significantly associated with U-AGT ( β = −0.31, p = 0.044) and U-Alb ( β = −0.25, p = 0.025) only at night. Conclusion: Impaired nighttime melatonin secretion may be associated with nighttime intrarenal RAS activation and renal damage in CKD patients. [ABSTRACT FROM AUTHOR]

The aldosterone-mineralocorticoid receptor (MR) system serves as the major regulator of fluid homeostasis, and is an important drug target for the treatment of hypertension, heart failure, and chronic kidney disease. While the ligand aldosterone plays a central role in facilitating MR activity, recent studies have revealed that MR signaling is modulated through distinct mechanisms at the levels of the receptor and the downstream targets. Notably, phosphorylation of the ligand-binding domain in MR regulates the ability of the receptor to bind to ligand in renal intercalated cells, providing an additional layer of regulation that allows the cell-selective control of MR signaling. These mechanisms are involved in the context-dependent effects of aldosterone in the distal nephron. In this article, the recent progress in the understanding of mechanisms regulating the action of aldosterone is discussed, focusing on the connecting tubules and collecting duct in the kidney. [ABSTRACT FROM AUTHOR]

Background: The impact of renin-angiotensin system blockade (RASB) on the incidence of end-stage renal disease (ESRD) remains unclear in IgA nephropathy (IgAN). Methods: This study assessed associations between RASB treatment and the incidence of ESRD in IgAN using propensity score approaches. We retrospectively analyzed 1273 patients with IgAN biopsied between 1979 and 2010. Propensity scores were calculated using logistic regression. Associations between RASB and ESRD were examined using a Cox regression model adjusted by inverse probability of treatment weighted, regression, stratification and matching. Results: During follow-up (median 5.1 years), 130 patients developed ESRD. With Cox regression adjusted by inverse probability of treatment weighted, RASB use was significantly associated with a lower risk of ESRD (hazard ratio 0.58; 95 % confidence interval 0.42-0.80). Significant associations were observed for other propensity score-based approaches. In stratified analysis, a beneficial association between RASB and ESRD was observed in patients ≥35 years, with hypertension, reduced estimated glomerular filtration rate (<60 mL/min/1.73 m), mesangial proliferation and segmental glomerulosclerosis ( P for interaction <0.05), and tended to be greater in patients with proteinuria (≥1.0 g/24 h), extracapillary proliferation and receiving methylprednisolone pulse therapy ( P for interaction <0.10). Conclusion: Treatment with RASB was associated with a lower incidence of ESRD in the real-world practice of IgAN. [ABSTRACT FROM AUTHOR]

Background: Renin-angiotensin system (RAS) activation increases angiotensin II production stimulating profibrotic factors, especially in the setting of chronic kidney disease. Nephrogenic systemic fibrosis (NSF) has been associated with gadolinium (Gd) exposure and renal failure. RAS involvement in NSF is unclear compared to transforming growth factor beta and Smad. RenTag mice were chosen to investigate the role of RAS in NSF-like dermal fibrosis because they demonstrated dermal fibrosis at birth, perturbations of RAS in subcutaneous tissue, and renal failure within 4 weeks of age. Methods: Wild-type and RenTag mice were injected weekly with a supratherapeutic dose of intravenous gadodiamide (3.0 mmol/kg body weight) and killed at 12 weeks of age for skin and kidney histology. Results: RenTag mice had elevated BUN levels, pitted kidneys, and glomerular damage. RenTag mice skin revealed an increased density of fibroblasts, no mucopolysaccharide deposits, and increased collagen fibril density regardless of Gd exposure. Skin and kidney histopathology of wild-type mice were normal regardless of Gd exposure. CD34 positivity was higher in RenTag compared to wild-type. Conclusions: Since RenTag dermal lesions remained unchanged after gadolinium exposure in the setting of renal failure, this animal model suggests perturbations of subcutaneous RAS may be involved in Gd-naïve dermal fibrosis. [ABSTRACT FROM AUTHOR]

Background: Several studies have demonstrated that spironolactone has an anti-albuminuric property in diabetic nephropathy. As an adverse event, spironolactone often induces the elevation of creatinine levels with hypotension and hyperkalemia. Therefore, we aimed to evaluate the efficacy and safety of spironolactone in Japanese patients with type 2 diabetes treated with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Methods: Fifty-two Japanese patients with diabetic nephropathy and albuminuria (100 mg/gCr-2000 mg/gCr) treated with renin-angiotensin system (RAS) blockade were enrolled in a prospective, randomized, open-label study. The patients were subjected to add-on treatment with spironolactone 25 mg once daily and compared with matched controls for 8 weeks. The primary outcome was a reduction in the rate of albuminuria at 8 weeks compared with the baseline value. This study was registered with UMIN Clinical Trials Registry (000008016). Results: Albuminuria was reduced by 33 % (95 % confidence interval: 22-54; P = 0.0002) at 8 weeks with spironolactone. In the spironolactone group, blood pressure tended to lower and the estimated glomerular filtration rate (eGFR) was significantly decreased compared to those in the control group. When adjusted by systolic blood pressure and eGFR, spironolactone treatment still showed a significant effect on albuminuria reduction in a linear mixed model (coefficient ± standard error; 514.4 ± 137.6 mg/gCr, P < 0.0005). No patient was excluded from the study because of hyperkalemia. Conclusions: Spironolactone reduced albuminuria along with conventional RAS inhibitors in patients with diabetic nephropathy. Our study suggests that spironolactone exerts anti-albuminuric effects independent of systemic hemodynamic alterations. [ABSTRACT FROM AUTHOR]

Background: All components of the renin-angiotensin system (RAS) are abundantly synthesized in the developing kidney, suggesting that the RAS plays an important role in renal development. To examine this system in human neonates, we measured urinary angiotensinogen levels in preterm and full-term neonates and examined the relationship between urinary angiotensinogen levels and gestational age. Methods: Urine and plasma samples were collected from 20 preterm and 18 full-term neonates at birth. Angiotensinogen levels were measured using enzyme-linked immunosorbent assay. Results: Plasma angiotensinogen concentrations were not increased in preterm neonates compared with that in full-term neonates ( P = 0.7288). However, the urinary angiotensinogen-to-creatinine ratio was significantly higher in preterm neonates compared with that in full-term neonates ( P = 0.0011). Importantly, the urinary angiotensinogen-to-creatinine ratio dropped significantly with increasing gestational age ( P = 0.0010), whereas the plasma angiotensinogen concentration was not correlated with gestational age ( P = 0.7814). Conclusions: These results suggest that urinary angiotensinogen levels may indicate the involvement of intrarenal RAS activation in prenatal renal development. [ABSTRACT FROM AUTHOR]

Both angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin II receptor blocker have been recognized as renin-angiotensin system (RAS) inhibitors. These two RAS inhibitors are rarely recognized as drugs with distinct pharmacological effects in the clinic or most clinical trials. Some preclinical basic research and clinical trials indicate that ACE-I might display superior organ-protective effects, especially anti-fibrotic effects. Such anti-fibrotic effects of ACE-I could be associated with an endogenous anti-fibrotic peptide, N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP). In this review, we focused on the anti-fibrotic effects of RAS inhibition and the endogenous anti-fibrotic peptide AcSDKP. [ABSTRACT FROM AUTHOR]

Background: Applying a direct renin inhibitor (DRI) to advanced stage chronic kidney disease (CKD) patients is a matter of controversy. The purpose of this study was to evaluate the effect of the DRI, aliskiren, in patients with therapy-resistant hypertension undergoing hemodialysis (HD). Methods: The study was a prospective, randomized multicenter trial exploring the antihypertensive effect of aliskiren in comparison with amlodipine, a calcium channel blocker, in patients undergoing HD. A total of 83 participants whose blood pressure (BP) had previously been treated with more than one antihypertensive agent and not having achieved the BP goal of <140/90 mmHg were randomly assigned to either aliskiren 150 mg or amlodipine 5 mg as an add-on therapy. Results: A significant decrease in pre-dialysis clinic BP and home BP was found only in the amlodipine group and not in the aliskiren group. In contrast, there was a significant decrease in atrial natriuretic peptide (ANP) in the aliskiren group but not in the amlodipine group. N-terminal pro-B-type natriuretic hormone remained unchanged in both groups. Aliskiren significantly reduced angiotensin I and II, plasma renin activity, and increased plasma renin content. However, such changes were not observed in the amlodipine group. Conclusion: Amlodipine, not aliskiren, effectively reduces BP in CKD patients with refractory hypertension undergoing HD. Aliskiren suppresses the renin−angiotensin system and reduces ANP. Whether the DRI is beneficial in improving cardiovascular events in patients undergoing HD remains to be elucidated in future studies. [ABSTRACT FROM AUTHOR]

Proportions of elderly aged ≥65 and ≥75 within Japan will increase to 30 and 20 %, respectively, in 2025, when 'Baby-Boom Generations' will reach the age of 75 years. Okabayashi and colleagues report that even in elderly patients with IgA nephropathy (IgAN), immunosuppressive treatment can reduce proteinuria, with no adverse events. Their findings remind us of recent finding from STOP-IgAN study; additional immunosuppressive therapy to intensive supportive care [specifically renin-angiotensin system (RAS) inhibitors (RASi)] did not improve the outcome. If STOP-IgAN makes doctors believe that immunosuppression is not necessary, many patients could lose opportunity to eliminate their kidney disease. Indeed, we have experienced patients with IgAN, who despite hematuria, could not undergo renal biopsy or immunosuppressive treatment at another facility because of low proteinuria, and exhibited advanced lesions in their renal biopsy at our institution. The discrepancy between Okabayashi's and STOP-IgAN study was derived not only from differences in population age (≥60 years vs. 18-70 years). STOP-IgAN excluded the crescentic IgAN, whereas Okabayashi et al. found active manifestations (hematuria, mesangial proliferation, and cellular/fibrocellular crescent). Therefore, immunosuppressive therapy is required even in elderly patients. In STOP-IgAN, RASi were used first, and then immunosuppressive agent was additionally used. RASi has important implications to reduce glomerular capillary pressure and to suppress the intrarenal RAS activity. However, immunosuppressant should be administered initially to cure hematuria. In fact, microscopic-hematuria was resolved in only 16 and 42 % of two-assigned groups in STOP-IgAN, respectively. Okabayashi et al. provided a timely message regarding the significance of immunosuppressive treatment of IgAN. [ABSTRACT FROM AUTHOR]

Background: The renin-angiotensin-aldosterone system (RAAS) plays pivotal roles in the pathogenesis of chronic kidney disease (CKD) progression. Aliskiren, a direct renin inhibitor, inhibits the rate-limiting step of the RAAS without any alternative pathway. It is proven to reduce albuminuria in CKD patients treated with angiotensin blockade. However, there are few reports which evaluate the advantage of aliskiren as the first-line drug against CKD progression in RAAS-activated hypertensive patients. Methods: Tsukuba hypertensive mice (THM), double transgenic mice carrying both the human renin and human angiotensinogen genes, were fed a high-salt diet and treated with hydraladine, ramipril and aliskiren for 10 weeks. Blood pressure and urinary albumin excretion were measured every 2 weeks during the experimental period. We evaluated renal histological changes and gene expression. Plasma angiotensin concentration was measured to evaluate the RAAS inhibitory effect. Results: High-salt-loaded THM showed severe hypertension and renal injury. All antihypertensive drugs suppressed blood pressure and prevented renal disease progression. RAAS blockade showed a higher renoprotective effect than hydraladine despite an equivalent blood pressure lowering effect. Aliskiren exhibited even stronger renoprotection than ramipril. Plasma angiotensin concentration was increased in THM fed both normal salt and high salt. Hydraladine did not alter the plasma angiotensin concentration. Ramipril significantly decreased angiotensin II concentration. Aliskiren treatment almost completely suppressed angiotensin I and resulted in lower angiotensin II concentration than ramipril treatment. Conclusion: Aliskiren prevents renal disease progression by suppressing both angiotensin I and II in RAAS-activated pathology. Our data suggest the application of a renin inhibitor for preventing kidney disease progression in CKD patients. [ABSTRACT FROM AUTHOR]

Atheromatous renal artery stenosis (ARAS), a lesion of systemic atherosclerotic disease, is the leading cause of stenotic lesions in the renal artery, followed by fibromuscular dysplasia, a primary abnormality of the renal artery. As a result of several clinical trails, which failed to show an additional benefit of renal revascularization to medical therapy in ARAS, the treatment of ARAS has shifted, and renal revascularization is less commonly performed for ARAS. However, it is recognized that renal revascularization benefits some patients with ARAS. Advances in imaging modalities would allow more frequent detection of ARAS in a society with a growing elderly population, a group with an increased prevalence of systemic atherosclerotic disease. Therefore, it is imperative to identify the patients with ARAS who could benefit from renal revascularization. This review presents a strategy for the treatment of ARAS based on the results of our analysis. [ABSTRACT FROM AUTHOR]

Background: Increasing evidence indicates that locally blocking renin-angiotensin system activity exerts a beneficial effect on glomerulonephritis (GN) progression leading to irreversible glomerulosclerosis. This is the first study on the pharmacological effect of the renal delivery of aliskiren, a direct renin inhibitor, in a progressive model of anti-Thy-1 GN. Methods: Local blockade of renin activity was accomplished by subrenal capsular implantation of a collagen sponge with aliskiren. The pharmacological effect was evaluated by semiquantitative and quantitative analysis of immunohistological findings and by analysis of glomerular microcirculation using an intravital microscope system. Results: Quantitative mesangial matrix analysis showed that local treatment with aliskiren significantly suppressed mesangial matrix expansion and ameliorated the glomerular sclerotic index in the progressive model of ATS GN. Immunofluorescent studies revealed that renin expression at the juxtaglomerular region was enhanced in the ATS + aliskiren group, and pathological expressions of α-smooth muscle cell actin and type I collagen in ATS GN were remarkably decreased by local treatment with aliskiren. Furthermore, local delivery of aliskiren significantly improved glomerular blood flow levels. Conclusion: This study revealed that renally delivered aliskiren has a renoprotective effect on potentially progressive glomerulosclerosis. [ABSTRACT FROM AUTHOR]

Recently, there has been a paradigm shift away from an emphasis on the role of the endocrine (circulating) renin−angiotensin system (RAS) in the regulation of the sodium and extracellular fluid balance, blood pressure, and the pathophysiology of hypertensive organ damage toward a focus on the role of tissue RAS found in many organs, including kidney. A tissue RAS implies that RAS components necessary for the production of angiotensin II (Ang II) reside within the tissue and its production is regulated within the tissue, independent of the circulating RAS. Locally produced Ang II plays a role in many physiological and pathophysiological processes such as hypertension, inflammation, oxidative stress, and tissue fibrosis. Both glomerular and tubular compartments of the kidney have the characteristics of a tissue RAS. The purpose of this article is to review the recent advances in tissue RAS research with a particular focus on the role of the glomerular RAS in the progression of renal disease. [ABSTRACT FROM AUTHOR]

Background: The adaptation of steroid therapy and the effect of renin-angiotensin-aldosterone system inhibitors (RASIs) for advanced immunoglobulin A nephropathy (IgAN) patients with impaired renal function are still controversial. Methods: We divided 63 IgAN patients with an estimated glomerular filtration rate (eGFR) of <60 ml/min/1.73 m and proteinuria ≥ 0.5 g/day into two groups: the RASI group (RASI, n = 33), treated with RASIs alone; and the combination group (COMBI, n = 30), treated with corticosteroids and RASIs. We analyzed the clinical and histological background, renal survival rate, and the risk factors for progression. Results: Renal function (mean eGFR: COMBI 46.4 vs. RASI 47.0 ml/min/1.73 m), the amount of proteinuria (median: COMBI 1.39 vs. RASI 1.17 g/g creatinine) and histological backgrounds were not significantly different between the groups, but urinary red blood cells (U-RBCs) were significantly higher in the COMBI group than in the RASI group (median: COMBI 30.0 vs. RASI 10.0 counts/high-power field, P = 0.0171). The serial change in proteinuria did not differ until 5 years after treatment, but U-RBCs were significantly decreased in both groups ( P < 0.0001), and eGFR was significantly decreased in the RASI group ( P < 0.001) but not in the COMBI group. The results for each year after treatment did not differ significantly between both groups. The renal survival rate was not significantly different between the groups. There was no independent risk factor for progression by Cox regression analysis. Conclusion: Combination therapy with steroids and RASIs was not superior to monotherapy with RASIs for advanced IgAN with impaired renal function. [ABSTRACT FROM AUTHOR]

Lupus nephritis is a common complication of systemic lupus erythematosus (SLE) which is associated with significant morbidity and mortality. The concept of two phases of therapy for lupus nephritis, such as an induction phase and a maintenance phase, is widely accepted. Since the renal involvement in SLE is heterogeneous, the treatment of lupus nephritis is governed by its pathological type and ranges from nonspecific measures, such as maintenance of adequate blood pressure control and blockade of the renin-angiotensin-aldosterone system, to the use of immunosuppressive agents. Cyclophosphamide (CYC) in combination with prednisone has been the standard method of treatment of the proliferative forms of lupus nephritis. However, the high rates of progression to end-stage renal disease coupled with the adverse effects of CYC and prednisone have led to an intensive search for more effective and less toxic therapies for lupus nephritis. We review the options available for the treatment of proliferative and membranous lupus nephritis and summarize the results of recently published clinical trials that add new perspectives to the management of kidney disease in SLE. [ABSTRACT FROM AUTHOR]

We report a case of acute kidney injury (AKI) caused by a novel direct renin inhibitor, aliskiren. A 43-year-old Japanese man with dilated cardiomyopathy on cardiac resynchronization therapy with defibrillator and chronic kidney disease (CKD) was started on aliskiren in addition to enalapril, carvedilol, furosemide, and spironolactone for worsening cardiac function suggested by the elevation of serum brain natriuretic peptide. After 1 month, he noticed general malaise, loss of appetite and his serum creatinine level increased from 2.0 to 7.24 mg/dL. He had no evidence of exacerbation of hemodynamic instability (heart failure or hypotension) or post-renal cause of AKI. Although a cessation of aliskiren did not ameliorate AKI, renal function returned to baseline after withholding enalapril. Careful monitoring is necessary when aliskiren is used in patients with CKD and/or significant systolic dysfunction since it can cause normotensive ischemic AKI, especially when there is a concomitant use of other renin-angiotensin-aldosterone system inhibitors. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study was to investigate the factors influencing serum parathyroid (PTH) levels, including medications for treating chronic kidney disease-mineral and bone metabolism disorder (CKD-MBD) in patients with end-stage renal disease. Methods: We enrolled 1,076 patients in nine Japanese facilities who had begun hemodialysis (HD) due to ESRD. We investigated the relationships between intact PTH (iPTH) levels and clinical parameters and medications just prior to beginning HD. Results: Significant decreases in serum iPTH levels were seen in males, in the presence of diabetes mellitus (DM), and with administration of renin-angiotensin system inhibitors (RASIs). Significant correlations were found between serum calcium and iPTH levels. In the patients administered RASIs, there was a significant decrease in serum iPTH levels with DM, male gender, and administration of active vitamin D sterols (VDs) compared with those not administered RASIs, although serum-corrected calcium levels were not different. Multiple regression analysis found gender, age, presence of DM, and serum calcium and phosphate levels to be significant contributing factors. In addition, administration of angiotensin II receptor blockers (ARBs) may also be a contributing factor to iPTH levels at the beginning HD ( p = 0.050). Conclusions: In this study, serum iPTH levels were related to administration of ARBs besides gender, age, the presence of DM and serum calcium levels. Our study suggests that the RA system involve serum iPTH levels in uremic patients. [ABSTRACT FROM AUTHOR]

Background: The aim of his study was to compare the efficacy of pioglitazone with metformin on the reduction of albuminuria in type 2 diabetic patients with hypertension and microalbuminuria treated with renin-angiotensin system inhibitors (RAS-Is). Methods: The open-label, randomized trial was performed in type 2 diabetic patients with hypertension and microalbuminuria. On the basis of the treatment with RAS-Is, 68 patients with microalbuminuria received either pioglitazone (15-30 mg/day; n = 32) or metformin (500-750 mg/day; n = 31) for 52 weeks. Urinary albumin-to-creatinine ratio (UACR) was measured every 12 weeks. Results: After 52 weeks of treatment, the changes in the log-UACR from baseline were −8.3% in the pioglitazone group and +4.2% in the metformin group ( p = 0.01), with similar glycemic and blood pressure changes. Conclusion: The combination of pioglitazone and RAS-Is showed therapeutic benefit in the reduction of urinary albumin excretion for type 2 diabetic patients with hypertension and microalbuminuria. [ABSTRACT FROM AUTHOR]

Background: We previously showed that there are marked geographic differences in the incidence of end-stage renal disease (ESRD) within Japan. In addition, the use of renin-angiotensin system inhibitors was found to be inversely correlated with the increasing ESRD rate. It was recently demonstrated that the incidence of ESRD due to diabetic nephropathy is declining in both Europe and USA. Therefore, we investigated the increasing ESRD rate and its geographic difference in Japan. Methods: Each year, the Japanese Society for Dialysis Therapy reports the numbers of patients initiating maintenance dialysis therapy in each prefecture of Japan. We used old (1984-1991) and recent (2001-2008) data to compare the increasing ESRD rate, which was estimated from the slope of the regression line of the annual incidence corrected for population, between the two periods in 11 regions of Japan. Results: Increasing ESRD rate almost halved, from 11.1 ± 5.6 to 5.4 ± 0.7/million per year from the old to the recent period. Deceleration of the increasing ESRD rate from the old to the recent period was correlated with the incidence in the old period across 11 regions ( r = 0.81, p < 0.003); i.e., the deceleration was greater in the regions where ESRD incidence had been higher. Whereas the increasing ESRD rate was significantly different among regions in the old period, this was not the case in the recent period, resulting in uniformity throughout Japan. Conclusions: The increasing ESRD rate is slowing in Japan, and its geographic differences, previously observed, have disappeared. [ABSTRACT FROM AUTHOR]

Background: The intrarenal renin−angiotensinogen system (RAS) plays a major role in the progression of chronic kidney disease. Urinary angiotensinogen (UAGT) provides a specific index of the intrarenal RAS status. This study was conducted to find the role of UAGT as a predictive marker in patients with immunoglobulin A nephropathy (IgAN). Methods: Thirty-six patients with IgAN, 14 non-IgAN and 15 healthy controls were included. The UAGT concentration was measured using human ELISA kits and adjusted by urinary creatinine. Results: UAGT levels were significantly higher in patients with IgAN and non-IgAN than in healthy subjects (104.96 vs. 6.71 ng/mgCr, p < 0.01). Using univariate regression analysis, UAGT was found to correlate with the urine protein-to-creatinine ratio (UPCR), serum creatinine, and systolic and diastolic blood pressure in patients with IgAN. Multivariate regression analysis revealed that UAGT correlated positively with UPCR. Patients with levels of UAGT >100 ng/mgCr showed higher serum creatinine after treatment than patients with UAGT levels <100 ng/mgCr. Conclusion: This study showed that UAGT levels are increased and correlate positively with the UPCR in IgAN. Patients with high levels of UAGT may have poor renal function following treatment. [ABSTRACT FROM AUTHOR]

im: IgA nephropathy (IgAN) is a very common glomerulonephritis among young adults, but the best therapeutic approach has not been fully elucidated. This study evaluated the effect of two different treatment regimes in IgAN, steroids alone or in combination with azathioprine. Methods: Among 122 patients with primary IgA nephropathy diagnosed in the 2000-2007 period, 22 fulfilled the inclusion criteria for the study: estimated glomerular filtration rate (eGRF) ≥30 ml/min/1.73 m, urine protein (Upr) ≥1 g/24 h, blood pressure (BP) <130/80 mmHg, and previous treatment with renin-angiotensin system inhibitors (RAASi) and polyunsaturated fatty acids (PFA) for at least 6 months. Patients were randomized to receive either methylprednisolone alone (MP group) or MP in combination with azathioprine (MP + Aza group) for 12 months, while treatment with RAASi + PFA continued unchanged in both groups. Results: At the completion of the trial, renal function in the MP group remained stable, eGFR from 52 ± 26.7 to 53.6 ± 27.3 ml/min/1.73 m, p = NS, and Upr decreased from 2.4 ± 0.9 to 0.8 ± 0.5 g/24 h, p < 0.001. In the MP + Aza group, eGFR slightly increased from 57.4 ± 28.7 to 66 ± 31 ml/min/1.73 m, p = NS, and Upr decreased from 2.4 ± 1 to 0.7 ± 0.7 g/24 h, p < 0.001. Four patients from the MP group with partial remission at the end of the trial had a complete response when converted to Aza. Eleven patients (5 from the MP and 6 from the MP + Aza group) relapsed after stopping treatment and were restarted on lower doses. Conclusions: Both, steroid treatment alone and steroids in combination with azathioprine seem to be effective in reducing the severity of proteinuria and stabilizing renal function in IgAN. Patients who do not respond to steroids may have a better response with the combination of steroids and azathioprine. [ABSTRACT FROM AUTHOR]

Familial lecithin-cholesterol acyltransferase (LCAT) deficiency (FLD) is a rare genetic disorder of lipid metabolism, characterised by low plasma HDL cholesterol, proteinuria, haemolytic anaemia and corneal opacities. Usually renal disease progresses during the third decade of life to renal failure; however the pathogenesis of renal disease is not well understood. In this study we describe treatment of renal disease in two siblings with FLD. The proband WX at the age of 31 years presented proteinuria and ankle oedema during her third pregnancy. Diagnosis of FLD was based on a renal biopsy with characteristic serpiginous fibrillar deposits under electron microscopy, markedly decreased HDL cholesterol, esterified cholesterol levels and LCAT activity, confirmed by molecular analysis. After 3 years her proteinuria increased and she received an ACE inhibitor to which she responded well. During further increases of proteinuria she additionally received methylprednisolone and her proteinuria decreased. This long-term observation indicates the efficacy of corticosteroids and renin−angiotensin−aldosterone system blockers in the treatment of proteinuria in patients with FLD. The results suggest the role of inflammatory processes as well as dyslipidemia in the pathogenesis of glomerular disorders in LCAT-deficient patients. [ABSTRACT FROM AUTHOR]

The renin-angiotensin-aldosterone system plays a pivotal role in regulation of blood pressure and electrolyte homeostasis and is a target in the treatment of hypertension and renal diseases. However, the factors correlated with plasma renin activity (PRA) are unclarified in general Japanese population. To examine this point, we conducted a community-based cross-sectional study. Subjects of this study were 2,056 individuals (mean age, 61 years; 934 men; 1,122 women) over 40-year-old without antihypertensive medication in Takahata town, Japan. PRA was measured by radioimmunoassay. Estimated 24-h urine sodium (e24hUNa) and potassium excretion were calculated from morning spot urine. The median value of PRA was higher in men compared to women (1.1 ng/ml/h vs. 0.7 ng/ml/h, P < 0.001). The increased PRA (>2.0 ng/ml/h) were detected in 248 men (26.3%) and 142 women (12.7%). One-factor analysis of variance showed that PRA was correlated with blood pressure, uric acid, hemoglobin, total protein, total cholesterol, low-density lipoprotein cholesterol, serum adiponectin and e24hUNa in men. In women, PRA was correlated with age, blood pressure, total protein, high-density lipoprotein cholesterol (HDL-C), serum insulin, e24hUNa and obesity. Multivariate logistic regression analysis showed that high PRA (>2.0 ng/ml/h) was independently associated with low blood pressures, low e24UNa and high serum total protein both in men and women, smoking only in men and high HDL-C only in women, respectively. This study revealed that PRA was higher in men than women and was associated negatively with blood pressures and urine sodium excretion, and positively with total protein, smoking and HDL-C in Japanese population. [ABSTRACT FROM AUTHOR]

Continuous ambulatory peritoneal dialysis is a well-accepted treatment for end-stage renal disease, but its long-term success is limited. Peritoneal sclerosis is still one of the most important complications of long-term peritoneal dialysis and the low biocompatibility of peritoneal dialysis solutions plays a major role in the development of such sclerosis. In this review, we summarize recent experimental data about the biocompatibility of peritoneal dialysis solutions. [ABSTRACT FROM AUTHOR]

In this study the effect of losartan and enalapril on the reduction of DNA damage was evaluated in regard to renin-angiotensin system (RAS) polymorphisms. After determination of genotypes of RAS polymorphism by PCR, 64 renal transplant recipients were randomly allocated to one of four groups: the first and second groups were treated with E (E+: 10 mg/day) and L (L+: 50 mg/day) alone, respectively. The third group received E+L (E+L+: 10 + 50 mg/day), and the forth group received no medication (E−L−). The subjects were followed for 8 weeks. After a 2-week washout period, the E group changed to L and vice versa as a cross-over design. They were followed for another 8 weeks. Before and after treatment, we checked 8-OHdG and malondialdehyde (MDA) as biomarkers of DNA damage and lipid peroxidation, respectively. 8-OHdG levels were significantly decreased after treatment in the E+L+ and L+ groups ( P < 0.001, P = 0.001, respectively). Only the TT genotype of AGT had the most antioxidative role regarding the treatment ( P = 0.01). We found a remarkable correlation between MDA and DNA damage levels before and after intervention ( r = 0.48, P < 0.001; r = 0.35, P = 0.006). The protective effects of L+ and E+L+ on DNA breaks are surprising regarding the RAS polymorphisms. [ABSTRACT FROM AUTHOR]

A 77-year-old man with a history of hypertension and hyperuricemia was admitted to our hospital complaining of limb weakness, persistent constipation, and worsening hypertension. He had been taking a Chinese herbal remedy for allergic rhinitis for the past 10 years, together with an angiotensin-converting enzyme inhibitor (ACE-I; enalapril, 20 mg daily). After the dosage of enalapril had been reduced to 10 mg daily about 1½ years before the current admission, he had developed persistent constipation. Therefore, he had started taking another traditional Chinese herbal remedy, a laxative, for the constipation, about 4 months prior to this hospitalization. Laboratory data on admission demonstrated marked metabolic alkalosis with severe hypokalemia associated with urinary wasting of potassium and chloride. A diagnosis of pseudoaldosteronism was made based upon his past history of exposure to various traditional Chinese medicines containing glycyrrhizin. Discontinuation of the Chinese remedies and supplementation of potassium successfully normalized the electrolyte imbalance and relieved all symptoms within a short time. The present case describes the occurrence of pseudoaldosteronism induced by a patient taking two traditional Chinese herbs, both containing glycyrrhizin, resulting in an overdose of this causative chemical agent. The development of pseudoaldosteronism appeared to be of particular interest with regard to the interaction of the renin-angiotensin-aldosterone (RAA) system with glycyrrhizin, in which an ACE-I retarded the development of pseudoaldosteronism. [ABSTRACT FROM AUTHOR]

The renin-angiotensin-aldosterone system has an important role in the progression of both diabetic and nondiabetic nephropathy. Angiotensin-converting enzyme inhibitors and angiotensin-II receptor blocker can effectively retard or halt this progression. However, their renoprotective effect is not enough, because approximately 20% of patients have a progressive course to endstage renal disease. There is now clear evidence that combination therapy of two agents is more antiproteinuric and, likely renoprotective, than each agent alone. However, several critical issues should be addressed before recommending it as standard treatment in chronic renal disease. [ABSTRACT FROM AUTHOR]

Background. Growth factors, cytokines, and the renin-angiotensin system (RAS) are involved in chronic allograft dysfunction. However, it is unclear whether clinical evaluations of TGFΒ1 and the RAS in longterm stable transplant patients can predict the development of chronic allograft dysfunction. Methods. Urinary TGFΒ1 excretion and the response of plasma renin activity (PRA) to angiotensin I converting-enzyme inhibition (ACE-I) were prospectively examined in transplant patients who had had stable graft function (n = 16) for at least 1 year after renal transplantation. Four-year follow-up studies were undertaken to evaluate the impact of these parameters on the development of chronic allograft dysfunction. Results. Urinary TGFΒ1 excretion and PRA response to ACE-I in renal transplant patients who developed chronic allograft nephropathy 4 years after the evaluations (n = 7) were significantly higher and greater, respectively, than these values in those who did not (n = 9; P ≪ 0.01). If the cutoff level for urinary TGFΒ1 excretion was 250 pg/min, the 4-year positive predictive value (PPV) with respect to the development of chronic allograft nephropathy was 83% and the negative predictive value (NPV) was 78% (sensitivity [sen.], 71%; specificity [sp.], 88%). If the cutoff level for PRA at 60 min after ACE-I was 4.0 ng/ml per h, the 4-year PPV was 71% and NPV was 75% (sen., 70%; sp., 75%). The stable transplant patients with high TGFΒ1 excretion and exaggerated PRA response showed significantly higher rates of chronic allograft dysfunction than those with low TGFΒ1 excretion and weak PRA response. Conclusions. This study demonstrates that some transplant patients with longterm stable graft function show increases in the activities of the TGFΒ system and the RAS. Evaluations of urinary TGFΒ1 excretion and PRA response to ACE-I present a possibility for predicting the development of chronic allograft dysfunction, with significant 4-year predictive values. [ABSTRACT FROM AUTHOR]

Background. Although it has been repeatedly shown that the oral carbonaceous absorbent AST-120 ameliorates the progression of chronic renal failure, the mechanisms remain unknown. Methods. Male Sprague-Dawley rats (6 weeks old), weighing 180–210 g, were 4/5 nephrectomized, and were divided into two groups: one given AST-120 (0.4 g/100 g body weight BW; n = 9) and the other not given AST-120 (n = 9). Body weight, blood pressure, and serum and urine chemistry, as well as the plasma components of the renin-angiotensin system, were measured for 22 weeks. Results. Proteinuria was significantly greater in the controls than in the AST-120 group (102 ± 22 vs 51 ± 7 mg/day at 22 weeks). Urea clearance was lower in the former (3.7 ± 0.4 vs 3.9 ± 0.4 ml/min). There were no differences in plasma renin activity (1.4 ± 0.3 vs 1.9 ± 0.4 mg/ml per h), or in angiotensin I (756 ± 119 vs 1042 ± 168 pg/ml) and II (35.1 ± 7.4 vs 46.6 ± 7.6 pg/ml) or angiotensin-converting enzyme activity (39.0 ± 2.4 vs 37.9 ± 2.2 IU/l) between the two groups. Protein intake, estimated from urinary urea appearance, was not different. Serum phosphate concentration (6.6 ± 0.3 vs 5.9 ± 0.3 mg/dl) was higher in the control than in AST-120, while the urinary phosphate excretion rate (31.5 ± 0.8 vs 28.1 ± 1.8 mg/day) tended to be lower in the latter. Conclusions. AST-120 retarded the progression of renal failure in the 4/5 renal ablation model without affecting the plasma renin-angiotensin system or protein intake, both of which were the most important risk factors for the progression of renal failure. We hypothesize that the renal protective effects of the oral absorbent AST-120 may be, at least in part, due to its lowering phosphate absorption from the diet as a phosphorus binder. [ABSTRACT FROM AUTHOR]

In the original publication, an error occurred in Table 4 (B), under Nighttime group. The value of "Nighttime Log U-AGT/Cr" for model 3 (under R = 0.68) was incorrectly published as 0.11. The correct value should read as -0.31. [ABSTRACT FROM AUTHOR]