Comparison of the Efficacy and Safety of Tacrolimus and Low-Dose Corticosteroid with High-Dose Corticosteroid for Minimal Change Nephrotic Syndrome in Adults.

BACKGROUND: Tacrolimus is used as a steroid-sparing immunosuppressant in adults with minimal change nephrotic syndrome. However, combined treatment with tacrolimus and low-dose steroid has not been compared with high-dose steroid for induction of clinical remission in a large-scale randomized study. METHODS: In this 24-week open-label noninferiority study, we randomized 144 adults with minimal change nephrotic syndrome to receive 0.05 mg/kg twice-daily tacrolimus plus once-daily 0.5 mg/kg prednisolone, or once-daily 1 mg/kg prednisolone alone, for up to 8 weeks or until achieving complete remission. Two weeks after complete remission, we tapered the steroid to a maintenance dose of 5-7.5 mg/d in both groups until 24 weeks after study drug initiation. The primary end point was complete remission within 8 weeks (urine protein: creatinine ratio <0.2 g/g). Secondary end points included time until remission and relapse rates (proteinuria and urine protein: creatinine ratio >3.0 g/g) after complete remission to within 24 weeks of study drug initiation. RESULTS: Complete remission within 8 weeks occurred in 53 of 67 patients (79.1%) receiving tacrolimus and low-dose steroid and 53 of 69 patients (76.8%) receiving high-dose steroid; this difference demonstrated noninferiority, with an upper confidence limit below the predefined threshold (20%) in both intent-to-treat (11.6%) and per-protocol (17.0%) analyses. Groups did not significantly differ in time until remission. Significantly fewer patients relapsed on maintenance tacrolimus (3-8 ng/ml) plus tapered steroid versus tapered steroid alone (5.7% versus 22.6%, respectively; P=0.01). There were no clinically relevant safety differences. CONCLUSIONS: Combined tacrolimus and low-dose steroid was noninferior to high-dose steroid for complete remission induction in adults with minimal change nephrotic syndrome. Relapse rates were significantly lower with maintenance tacrolimus and steroid compared with steroid alone. No clinically-relevant differences in safety findings were observed.

Sex-related differences in the intratubular renin-angiotensin system in two-kidney, one-clip hypertensive rats.

The intratubular renin-angiotensin system (RAS) is thought to play an essential role in hypertensive renal disease, but information regarding sex-related differences in this system is limited. The present study investigated sex differences in the intratubular RAS in two-kidney, one-clip (2K1C) rats. A 2.5-mm clip was placed on the left renal artery of Sprague-Dawley rats, and rats were euthanized 3 or 5 wk after the operation. Systolic blood pressure increased in 2K1C rats in both sexes but was significantly higher in male rats than in female rats, and an antihypertensive effect was not observed in 2K1C ovariectomized (OVX) female rats. Compared with male 2K1C rats, intratubular angiotensin-converting enzyme (ACE) and ANG II were repressed, and intratubular ACE2, angiotensin (1-7), and Mas receptor were increased in both kidneys in female 2K1C rats 5 wk after surgery. Comparison with male and female rats and intratubular mRNA levels of ACE and ANG II type 1 receptor were augmented in OVX female rats, regardless of the clipping surgery 3 wk postoperation. ANG II type 2 receptor was upregulated in female rats with or without OVX; thus, the ANG II type 1-to-type 2 receptor ratio was higher in male rats than in female rats. In conclusion, female rats were protected from hypertensive renal and cardiac injury after renal artery clipping. An increase in the intratubular nonclassic RAS [ACE2/angiotensin (1-7)/Mas receptor] and a decrease in the ANG II type 1-to-type 2 receptor ratio could limit the adverse effects of the classic RAS during renovascular hypertension in female rats, and estrogen is suggested to play a primary role in the regulation of intratubular RAS components.

Combination therapy of low-dose cyclosporine and steroid in adults with IgA nephropathy
.

BACKGROUND: A few clinical trials in IgA nephropathy (IgAN) have shown that cyclosporine A (CyA) had therapeutic efficacy in reducing proteinuria. MATERIALS AND METHODS: This is a retrospective study, and all cases were selected based on kidney biopsy-proven IgAN. We reviewed the data of IgAN patients in the glomerulonephritis registry at Kyung Hee University Medical center and collected data on 86 patients with urinary protein/Cr ratio (PCR; g/g) > 0.5 and estimated GFR (eGFR) of > 50 mL/min/1.73m2 who were treated with combination therapy of low-dose CyA plus low-dose steroid (C+P; n = 37) and high-dose steroid single therapy (P; n = 49). RESULTS: In the C+P group, the mean duration of therapy was 14.5 ± 13.1 months, and the mean duration of follow-up 66.2 ± 36.3 months. In the C+P group, the urine PCR levels significantly declined after treatment (< 0.05). After 6 months of treatment, 12 (32%) patients were in complete remission and 7 (19%) in partial remission in the C+P group, compared with 21 (42%) and 11 (22%) in the P group, respectively. Urine PCR levels were also significantly reduced in 12 patients in the C+P group who had initial urine PCR between 0.5 and 1.0. The degree of hematuria was significantly reduced after treatment in the C+P group. These effects of C+P therapy on proteinuria and hematuria were very comparable to high-dose P therapy. After 2 years, a decline in renal function, > 25% decrease in eGFR from baseline levels, developed in 3 (8.1%) in the C+P group, compared with 4 (8.2%) in the P group. The rate of decline in renal function during follow-up was -0.14 ± 0.40 mL/min/1.73m2/month in the C+P group compared with -0.12 ± 0.22 mL/min/1.73m2/month in the P group. There were no changes of mean eGFR during the first 24 months, but the eGFR significantly decreased at last follow-up in both groups. When patients in the C+P group were divided into progressive (n = 9) and nonprogressive (n = 28) groups, a significant reduction in the amount of proteinuria after treatment was observed in the nonprogressive group, in contrast to the progressive group. In the C+P group, there were no severe adverse effects, especially no acute renal impairment, requiring discontinuation of CyA in this study. The incidence of infection was much lower in the C+P group than that in the P group. The limitation is that CyA acts to nonspecifically reduce proteinuria, so it requires long-term follow-up off CyA therapy for more than 2 years to determine. CONCLUSION: Our retrospective uncontrolled study provides only weak evidence that combination therapy of low-dose C+P could be an alternative to high-dose P therapy and be safe in adult IgAN patients with relatively normal renal function and proteinuria of > 0.5 g/g. Development of safe and effective therapy is still a major challenge requiring well-controlled prospective studies with this or other combination therapies.

Potential urine proteomics biomarkers for primary nephrotic syndrome.

BACKGROUND: Nephrotic syndrome (NS) is a nonspecific kidney disorder, commonly caused by minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and membranous nephropathy (MN). Here we analyzed urinary protein profiles, aiming to discover disease-specific biomarkers of these three common diseases in NS. METHODS: Sixteen urine samples were collected from patients with biopsy-proven NS and healthy controls. After removal of high-abundance proteins, the urinary protein profile was analyzed by LC-MS/MS to generate a discovery set. For validation, ELISA was used to analyze the selected proteins in 61 urine samples. RESULTS: The discovery set included 228 urine proteins, of which 22 proteins were differently expressed in MCD, MN, and FSGS. Among these, C9, CD14, and SERPINA1 were validated by ELISA. All three proteins were elevated in MCD, MN, and FSGS groups compared with in IgA nephropathy and healthy controls. When a regression model was applied, receiver operating characteristic analysis clearly discriminated MCD from the other causative diseases in NS. CONCLUSIONS: We developed a disease-specific protein panel that discriminated between three main causes of NS. Through this pilot study, we suggest that urine proteomics could be a non-invasive and clinically available tool to discriminate MCD from MN and FSGS.

Sequential activation of the intrarenal renin-angiotensin system in the progression of hypertensive nephropathy in Goldblatt rats.

The intrarenal renin-angiotensin system (RAS) has an important role in generating and maintaining hypertension in two-kidney, one-clip (2K1C) rats. This study evaluated how various intrarenal RAS components contributed to hypertension not only in the maintenance period (5w; 5 wk after operation) but also earlier (2w; 2 wk after operation). We inserted a 2.5-mm clip into the left renal artery of Sprague-Dawley rats and euthanized them at 2w and 5w following the operation. Systolic blood pressure increased within 1 wk after the operation, and left ventricular hypertrophy occurred in 2K1C rats. At 2w, juxtaglomerular apparatus (JGA) and collecting duct (CD) renin increased in clipped kidney (CK) of 2K1C rats. The tubular angiotensin I-converting enzyme (ACE) was not changed, but peritubular ACE2 decreased in nonclipped kidney (NCK) and CK of 2K1C rats. At 5w, ACE and CD renin were enhanced, and ACE2 was still lessened in both kidneys of 2K1C rats. However, plasma renin activity (PRA) was not different from that in sham rats. In proximal tubules of CK, the ANG II type 1 receptor (AT1R) was not suppressed, but the Mas receptor (MasR) was reduced; thus the AT1R/MasR ratio was elevated. Although hypoxic change in CK could not be excluded, the JGA renin of CK and CD renin in both kidneys was highly expressed independent of time. Peritubular ACE2 changed in the earlier period, and uninhibited AT1R in proximal tubules of CK was presented in the maintenance period. In 2K1C rats, attenuated ACE2 seems to contribute to initiating hypertension while upregulated ACE in combination with unsuppressed AT1R may have a key role in maintaining hypertension.

Hyperuricemia-induced NLRP3 activation of macrophages contributes to the progression of diabetic nephropathy.

IL-1ß-secreting nucleotide-binding oligomerization domain protein 3 (NLRP3) inflammasomes play a pivotal role in triggering innate immune responses in metabolic disease. We investigated the role of soluble uric acid in NLRP3 inflammasome activation in macrophages to demonstrate the effect of systemic hyperuricemia on progressive kidney damage in type 2 diabetes. THP-1 cells, human acute monocytic leukemia cells, were cultured to obtain macrophages, and HK-2 cells, human renal proximal tubule cells, were cultured and stimulated with uric acid. In vivo, we designed four rat groups as follows: 1) Long-Evans Tokushima Otsuka (LETO); 2) Otsuka Long-Evans Tokushima Fatty (OLETF); 3) OLETF+high-fructose diet (HFD) for 16 wk; and 4) OLETF+HFD+allopurinol (10 mg/dl administered in the drinking water). Soluble uric acid stimulated NLRP3 inflammasomes to produce IL-1ß in macrophages. Uric acid-induced MitoSOX mediates NLRP3 activation and IL-1ß secretion. IL-1ß from macrophages activates NF-κB in cocultured proximal tubular cells. In vivo, intrarenal IL-1ß expression and macrophage infiltration increased in HFD-fed OLETF rats. Lowering the serum uric acid level resulted in improving the albuminuria, tubular injury, macrophage infiltration, and renal IL-1ß (60% of HFD-fed OLETF) independently of glycemic control. Direct activation of proximal tubular cells by uric acid resulted in (C-X-C motif) ligand 12 and high mobility group box-1 release and accelerated macrophage recruitment and the M1 phenotype. Taken together, these data support direct roles of hyperuricemia in activating NLRP3 inflammasomes in macrophages, promoting chemokine signaling in the proximal tubule and contributing to the progression of diabetic nephropathy through cross talk between macrophages and proximal tubular cells.

Anti-Phospholipase A2 Receptor Antibody as Prognostic Indicator in Idiopathic Membranous Nephropathy.

BACKGROUND: Anti-phospholipase A2 receptor antibody (PLA2R-Ab) is useful in diagnosing idiopathic membranous nephropathy (IMN). We investigated the clinical relevance of PLA2R-Ab enzyme-linked immunosorbent assay (ELISA) in patients with IMN. METHODS: We measured PLA2R-Ab with an ELISA kit from the serum of 160 patients with IMN (n = 93), secondary MN (n = 14) and other glomerulonephritis (n = 41) as well as healthy controls (n = 12) at the time of renal biopsy and investigated the correlation of titers of PLA2R-Ab with clinical parameters. RESULTS: PLA2R-Ab was positive in 41 of 93 patients (44.1%) with IMN. No samples from the patients with secondary MN and other glomerulonephritis or healthy controls were positive with the ELISA test. The PLA2R-Ab-positive patients showed severe disease activity and a low remission rate. The PLA2R-Ab titer positively correlated with proteinuria and was negatively associated with renal function and serum albumin. The patients with a high titer of PLA2R-Ab had significantly decreased remission rates. The cumulative probabilities of remission was significantly lower in patients with PLA2R-Ab (p = 0.01) and even so in patients with a high titer of PLA2R-Ab (p = 0.04). When we compared the ELISA titers with Western blot (WB) data of 43 patients who had been enrolled in our previous study, 18 and 30 patients were positive on ELISA (41.9%) and WB (69.8%), respectively. WB and ELISA had a concordance rate of 72.1% and were positively correlated (r = 0.590, p < 0.001). CONCLUSION: The presence, as well as a high titer, of PLA2R-Ab on ELISA was associated with poor prognosis of IMN. Assessment of PLA2R-Ab with ELISA is an easy and reliable tool for the diagnosis and guidance of therapeutic plans.

Impact of reduced vancomycin MIC on clinical outcomes of methicillin-resistant Staphylococcus aureus bacteremia.

Vancomycin has been a key antibiotic agent for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. However, little is known about the relationship between vancomycin MIC values at the higher end of the susceptibility range and clinical outcomes. The aim of this study was to determine the impact of MRSA bacteremia on clinical outcomes in patients with a vancomycin MIC near the upper limit of the susceptible range. Patients with MRSA bacteremia were divided into a high-vancomycin-MIC group (2 µg/ml) and a low-vancomycin-MIC group (≤1.0 µg/ml). We examined the relationship between MIC, genotype, primary source of bacteremia, and mortality. Ninety-four patients with MRSA bacteremia, including 31 with a high vancomycin MIC and 63 with a low MIC were analyzed. There was no significant difference between the presence of agr dysfunction and SCCmec type between the two groups. A higher vancomycin MIC was not found to be associated with mortality. In contrast, high-risk bloodstream infection sources (hazard ratio [HR], 4.63; 95% confidence interval [CI] = 1.24 to 17.33) and bacterial eradication after treatment (HR, 0.06; 95% CI = 0.02 to 0.17), irrespective of vancomycin MIC, were predictors of all-cause 30-day mortality. Our study suggests that a high-risk source of bacteremia is likely to be associated with unfavorable clinical outcomes, but a high vancomycin MIC in a susceptible range, as well as genotype characteristics, are not associated with mortality.

Association of C1q deposition with renal outcomes in IgA nephropathy.

BACKGROUND/AIMS: IgA nephropathy (IgAN) is characterized by a highly variable clinical course. It has been reported that histopathologic lesions are risk factors for the progression of IgAN. The aim of this study was to investigate the relationships between co-deposition of C1q, clinicopathological features, and renal outcomes in patients with IgAN. METHODS: This retrospective cohort study included 221 patients with primary IgAN who underwent renal biopsy at the Kyung Hee University Medical Center from January 1996 to December 2008. Patients were divided in two groups: C1qpositive and C1q-negative. Using propensity scores to minimize confounding factors, we selected 36 matched C1q-negative patients from among the 203 unmatched C1q-negative patients and compared them with the 18 C1q-positive patients. We evaluated baseline characteristics and the severity of histologic lesions. We expressed the average rate of monthly renal function decline as the slope of eGFR (ΔGFR/M). RESULTS: 18 patients with IgAN showed mesangial deposition of C1q (8.1%). The C1q-positive patients had higher mean systolic blood pressure values and more impaired renal function than the unmatched C1q-negative patients. However, this association was not seen when the C1qpositive patients were compared with the matched C1q-negative patients. The slope of eGFR (ΔeGFR/M) declined steeply in the C1q-positive group. The incidence of severe cases of tubulointerstitial inflammation (TII) and fibrosis (TIF) was also greater in the C1q-positive group than the unmatched C1qnegative group, while only the incidence of severe TIF was significantly greater in the C1q-positive group than the matched C1qnegative group. Biopsies from C1q-positive patients showed more intense IgA staining as well as positive rates of IgG and IgM staining than those of unmatched C1q-negative patients. However, compared with the matched C1q-negative group, only the IgG positive rate was significantly higher in the C1q-positive patients. Multiple regression analysis of C1q-positive and matched C1q-negative patients revealed that C1q deposition was a critical determinant of a poorer renal prognosis. CONCLUSIONS: Mesangial C1q deposition in the glomerulus is associated with a poor renal outcome and severe pathologic features in patients with IgAN. The deposition of C1q in IgAN could therefore serve as an indicator of a poor renal prognosis.

Aberrant recruitment and activation of T cells in diabetic nephropathy.

BACKGROUND/AIMS: Recent evidence has shown that an inflammatory process is involved in the development and progression of diabetic nephropathy. This study examined the impact of activated intrarenal lymphocytes in this inflammatory process. METHODS: We studied T cell recruitment in mice with streptozotocin (STZ)-induced diabetes by flow cytometry and immunohistochemistry. The kidney biopsy specimens from patients with type 2 diabetes mellitus and diabetic nephropathy were evaluated by immunohistochemistry. RESULTS: In flow cytometry, intrarenal CD3+ T cells were significantly increased in proteinuric mice at 20 weeks after STZ injection. However, the population of T cells and B cells in diabetic spleen was not different from that of control mice. Immunohistochemistry also showed a marked infiltration of interstitial CD4+, CD8+ T cells in diabetic kidney. Interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) mRNA expression was significantly increased in diabetic mouse kidney compared with controls. Interestingly, flow cytometry analysis of kidney-derived mononuclear cells from diabetic mice showed significantly increased production of IFN-γ and TNF-α by CD3+ T cells. Type 2 diabetic patients also showed a marked increase in CD4+, CD8+ and CD20+ cells in interstitium, and the number of CD4+ and CD20+ cells correlated with the amount of proteinuria. CONCLUSION: Our results clearly showed that aberrant intrarenal infiltration and the activation of T cells in interstitium are the underlying immunopathological mechanisms of diabetic kidney injury.

Gene polymorphisms of interleukin-17 and interleukin-17 receptor are associated with end-stage kidney disease.

BACKGROUND: Inflammation could be a causal factor in progression of chronic kidney disease. To date, there is convincing experimental and clinical evidence to support the notion that interleukin (IL)-17-producing T cells contribute to kidney injury in renal diseases. However, the genetic relationship between end-stage renal disease (ESRD) and the T-helper 17 pathway has never been studied. In this study, we hypothesized that polymorphisms of IL-17 or their receptors may be associated with ESRD. METHODS: A total of 290 nondiabetic ESRD patients and 289 normal controls were included. We analyzed 13 single nucleotide polymorphisms located within the four genes of IL17A, IL17E, IL17RA and IL17RB. RESULTS: The ESRD patients had a significantly higher allele frequency compared to control subjects for the IL17E rs10137082*C and IL17RA rs4819554*A alleles. Genotyping analysis demonstrated that 2 SNPs among 13 were significantly associated with ESRD after adjusting for age and sex, which were shown by IL17E rs10137082 (odds ratio (OR) 1.48 in codominant 1, OR 1.54 in dominant, OR 1.47 in log-additive) and IL17RA rs4819554 (OR 1.46 in codominant 1, OR 1.79 in codominant 2, OR 1.54 in dominant, OR 1.39 in log-additive). CONCLUSIONS: Two polymorphisms within the IL17E and IL17RA genes are associated with ESRD independent of age and sex. This is the first finding to suggest that genetic variations of IL17 genes affect the risk of development of ESRD.

Reducing serum uric acid attenuates TGF-ß1-induced profibrogenic progression in type 2 diabetic nephropathy.

BACKGROUND: The pivotal role of transforming growth factor-ß1 (TGF-ß1)-induced tubulointerstitial fibrosis in the progression of chronic kidney disease is an active topic of research. Recent evidence indicates that hyperuricemia is associated with increased TGF-ß1 and progressive tubulointerstitial injury. We examined the hypothesis that lowering serum uric acid attenuates TGF-ß1-induced profibrogenic tubular change in type 2 diabetic nephropathy. METHODS: KK-A(y)/Ta mice, an animal model of type 2 diabetes, were provided access to either regular drinking water or drinking water containing 10 mg/dl of allopurinol. Normal rat kidney epithelial cells were cultured and stimulated with 5 mM uric acid with or without allopurinol. RESULTS: Type 2 diabetic mice that received allopurinol exhibited smaller increases in urinary albumin:creatinine ratio than diabetic control mice, as well as attenuated TGF-ß1 and Smad pathway-induced profibrogenic tubular changes in diabetic kidneys. Allopurinol attenuated TGF-ß1-induced Smad pathway activation in tubular cells. These findings were related to increases in E-cadherin, and decreases in vimentin and α-smooth muscle actin. Uric acid-induced upregulation of TGF-ß1 depends on mitogen-activated protein kinase signaling. CONCLUSIONS: This is the first study to demonstrate that reducing serum uric acid has preventive effects against to profibrogenic progression in type 2 diabetic kidney disease. These findings suggest that lowering serum uric acid may be an effective therapeutic intervention to prevent the progression of type 2 diabetic kidney disease.

Real-time monitoring of the effects of telmisartan on angiotensin II-induced mechanical changes in live mesangial cells using atomic force microscopy.

BACKGROUND/AIMS: Recent studies have shown that angiotensin II (Ang II) type 1 receptor blockers (ARB) may provide renal protection independent of their blood pressure-lowering effect. However, evidence for this comes from indirect methods, such as genetic or protein expression studies. In this study, we hypothesized that telmisartan, a specific ARB, applied to Ang II-stimulated mesangial cell (MC) would exert a renoprotective effect via modulation of MCs' mechanical properties. METHODS: We investigated the effect of telmisartan on Ang II-induced changes in MCs utilizing real-time atomic force microscopy (AFM) imaging and force-distance curve measurements. RESULTS: Real-time AFM images of live MCs demonstrated that cells contracted towards the center after Ang II exposure, and telmisartan treatment abolished this change. Cellular spring constants showed that telmisartan prevented Ang II-induced MC stiffening (Ang II: 0.109 ± 0.019 N/m, Ang II + telmisartan: 0.051 ± 0.016 N/m, p < 0.005). Telmisartan-treated MCs had a significantly lower adhesion force than those of the control group (control: 0.49 ± 0.22 nN, telmisartan: 0.22 ± 0.06 nN, Ang II: 0.40 ± 0.25 nN, Ang II + telmisartan: 0.27 ± 0.14 nN, p < 0.005). These results demonstrate that the dynamic contraction and mechanical properties of Ang II-stimulated MCs are restored by telmisartan. CONCLUSIONS: We report for the first time the use of AFM force-distance curves on live MCs to directly monitor changes in surface adhesion and stiffness of cells after treatment with telmisartan in real time.

Relationship between glomerulomegaly and clinicopathologic findings in IgA nephropathy.

BACKGROUND: Large glomeruli are a common finding in the early stages of progressive renal disease. We studied the relationship between glomerular surface area (GSA) and clinicopathologic features of IgA nephropathy (IgAN), including renal outcome, to better understand the role of GSA in IgAN. METHODS: We analyzed renal biopsy specimens and clinical information from 34 patients with IgAN. Mean and maximal GSA were determined using a computed imaging analyzer. RESULTS: Mean GSA was 16,811 ± 4,671 µ2 in IgAN patients (n = 34). When we analyzed various clinical parameters of IgAN patients, there were significant correlations between mean or maximal GSA and age, body mass index (BMI), systolic and diastolic blood pressure, estimated glomerular filtration rate (eGFR), and pathologic findings including H.S. Lee' grades, interstitial fibrosis, and tubular atrophy. GSA did not show any relationship with the degree of hematuria and proteinuria. By multivariate regression analysis of age, BMI, blood pressure, H.S. Lee' grades, and eGFR as independent variables, mean GSA was associated with H.S Lee' grades and initial eGFR. The results for maximal GSA were the same as those for mean GSA. When we divided IgAN patients according to their mean levels of GSA, the group with larger GSA had higher blood pressure and H.S. Lee' grades and lower initial and final eGFR. More patients in the larger GSA group showed the decline in eGFR of more than 15 ml/min/1.73 m2 during the followup period compared with the smaller group. CONCLUSION: These results suggest that glomerular size, estimated by measuring GSA, is related to pathologic findings and renal function in IgAN. However, further investigation is required to determine if GSA can be used as a prognostic indicator of IgAN.

Attenuating effect of angiotensin-(1-7) on angiotensin II-mediated NAD(P)H oxidase activation in type 2 diabetic nephropathy of KK-A(y)/Ta mice.

ANG-(1-7) is associated with vasodilation and nitric oxide synthase stimulation. However, the role of ANG-(1-7) in type 2 diabetes mellitus is unknown. In this study, we examined the hypothesis that ANG-(1-7) attenuates ANG II-induced reactive oxygen species stress (ROS)-mediated injury in type 2 diabetic nephropathy of KK-A(y)/Ta mice. KK-A(y)/Ta mice were divided into four groups: 1) a control group; 2) ANG II infusion group; 3) ANG II+ANG-(1-7) coinfusion group; and 4) ANG II+ANG-(1-7)+d-Ala(7)-ANG-(1-7) (A779) coinfusion group. In addition, primary mesangial cells were cultured and then stimulated with 25 mM glucose with or without ANG II, ANG-(1-7), and A779. The ANG II+ANG-(1-7) coinfusion group showed a lower urinary albumin/creatinine ratio increase than the ANG II group. ANG-(1-7) attenuated ANG II-mediated NAD(P)H oxidase activation and ROS production in diabetic glomeruli and mesangial cells. ANG II-induced NF-κB and MAPK signaling activation was also attenuated by ANG-(1-7) in the mesangial cells. These findings were related to improved mesangial expansion and to fibronectin and transforming growth factor-ß1 production in response to ANG II and suggest that ANG-(1-7) may attenuate ANG II-stimulated ROS-mediated injury in type 2 diabetic nephropathy. The ACE2-ANG-(1-7)-Mas receptor axis should be investigated as a novel target for treatment of type 2 diabetic nephropathy.

Urinary angiotensinogen as a predictive marker in patients with immunoglobulin A nephropathy.

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.

Association between renin-angiotensin-aldosterone system-related genes and blood pressure in a Korean population.

AIMS. Blood pressure control is influenced by various genetic and environmental factors, and genetic susceptibility is important in the development of essential hypertension. Because the renin-angiotensin-aldosterone system (RAAS) has a key role in vasoconstriction, vasodilation, and sodium and electrolyte balance, it is central in blood pressure control and so is an appropriate target in hypertension treatments. The present study assessed the association of RAAS-related genes with blood pressure and hypertension in a Korean population. Single nucleotide polymorphisms (SNPs, n = 114) in nine RAAS-related genes (AGT, REN, ACE, ACE2, AGTR1, CYP11B2, NR3C2, MAS1, and CMA1) were assessed for their correlation with blood pressure and hypertension using genotype data of 8842 individuals from the Korea Association Resource subject pool. MAJOR FINDINGS. Linear regression analysis revealed a statistically significant association with blood pressure of 10 SNPs in six genes (ACE, ACE2, CYP11B2, NR3C2, MAS1, and CMA1). An additional hypertension case-control study identified 10 SNPs in NR3C2 and ACE that were linked to hypertension. PRINCIPAL CONCLUSION. Three SNPs (rs11737660, rs6810951, and rs10519963) in NR3C2 correlate with both blood pressure and hypertension. Genetic polymorphisms in RAAS-related genes appear to be associated with hypertension in a Korean population.

Serum interferon-γ and urinary monocyte chemoattractant peptide-1 are important factors in the pathogenesis of immunoglobulin A nephropathy.

BACKGROUND: Imbalance of T helper (Th) 1/2 cells has been shown to contribute to the development of immunoglobulin A nephropathy (IgAN). To address the inconsistent results on the role of Th1/Th2 polarization, we evaluated the levels of Th1/Th2 cytokines in various samples from patients with IgAN. METHODS: Thirty-one patients with biopsy-proven IgAN (age, 34.48 ± 12.10 years) and 25 healthy controls (age, 44.84 ± 13.72 years) were enrolled. We evaluated the relationship between the levels of Th1/Th2 cytokines and the response to glucocorticoid treatment. RESULTS: The levels of serum interferon-gamma (IFNγ) and urinary monocyte chemoattractant peptide (MCP)-1 were higher in the IgAN group than in the control group. The levels of MCP-1 in urine and secreted by peripheral blood mononuclear cells (PBMCs) were significantly different among three groups categorized based on daily proteinuria. The level of urinary MCP-1 was significantly correlated with proteinuria. The levels of urinary MCP-1, serum interleukin (IL)-4, IFNγ, and IL-2 secreted by PBMCs and intrarenal IL-1 messenger RNA (mRNA) were significantly correlated with the ratio of proteinuria at 6 months to baseline proteinuria in patients undergoing glucocorticoid treatment. MCP-1 mRNA and protein levels were significantly upregulated in mesangial cells stimulated with IFNγ among representative Th1/Th2 cytokines. CONCLUSION: IFNγ was shown to be a key cytokine in the pathogenic processes underlying IgAN, and its upregulation induced an increase in urinary MCP-1 production. These findings suggest that Th1 cytokines may play an important role in the development of IgAN.

The relationship between circulating fibroblast growth factor 23 and bone metabolism factors in Korean hemodialysis patients.

BACKGROUND: Fibroblast growth factor 23 (FGF-23) is a circulating factor that acts as a phosphaturic factor in the kidneys. It is also involved in several disorders of phosphate regulation and bone metabolism. We hypothesized that increased FGF-23 levels in patients with endstage renal disease (ESRD) on maintenance hemodialysis would be associated with increased bone demineralization, and we analyzed the relationship between FGF-23 levels and bone mineral density (BMD). METHODS: The serum level of FGF-23 was measured in this cross-sectional study, whose subjects consisted of 54 patients with ESRD on maintenance hemodialysis. Clinical parameters associated with hemodialysis and bone metabolism were measured. The relationship between serum FGF-23 and BMD and the factors affecting the serum level of FGF-23 were analyzed. RESULTS: Serum FGF-23 levels were significantly higher in ESRD patients on maintenance hemodialysis than in normal persons (2961.4 vs. 30 pg/ml). Multiple regression analysis showed that increasing FGF-23 levels were associated with serum phosphate (r = 0.684, P < 0.001), but not with BMD or other bone metabolism factors. Factors affecting log(10)FGF-23 included the serum calcium phosphate product (beta = 0.603) and K (t)/V (integrated fractional clearance expressed per dialysis, beta = -0.244). These results were also seen in an analysis of the correlations based on T score or gender. CONCLUSIONS: FGF-23 levels were positively associated with serum phosphate levels but were not correlated with BMD. The only factors affecting log(10)FGF-23 were the serum calcium phosphate product and K (t)/V. These findings suggest that FGF-23 may have no direct effect on bone mineralization, and further studies are warranted to examine the effects of FGF-23 on vitamin D metabolism.