Tenascin-C expression in renal biopsies from patients with tubulointerstitial nephritis and its relation to disease activity and prognosis.

Tenascin-C (TNC) is an extracellular matrix protein that is transiently expressed in close association with tissue remodeling in various organs. Expression of TNC in patients with tubulointerstitial nephritis (TIN) is not well-characterized. Using renal biopsy specimens from 25 patients with TIN and 8 patients with thin basement membrane disease (controls), we assessed immunohistochemical staining for TNC and investigated its relation with clinicopathologic data. TNC was undetectable in the controls, but TNC was observed in the interstitium of specimens from all patients with TIN, and strong TNC staining was detected within active tubulitis lesions. TNC was not principally expressed in glomeruli, and it was also absent from scar tissue. Comparison with Sirius red staining revealed that TNC was present where collagen fibers had not yet formed. The percent area of TNC within the interstitium (% TNC-positive area) showed a significant negative correlation with illness duration and significant positive correlations with the serum CRP level and eGFR aggravation, both of which reflect disease activity. On the other hand, no correlation was found between % TNC-positive area and eGFR recovery during 2 years of follow up. Examination of renal biopsy specimens from TIN patients revealed that TNC appears during the active stage of inflammation and then disappears with healing. This suggests that TNC expression reflects TIN disease activity, but not prognosis.

Relationship between electrical conduction and phasic left atrial function: P-wave signal-averaged electrocardiography and time-left atrial volume curve assessments using two-dimensional speckle-tracking echocardiography.

P-wave signal-averaged electrocardiography (P-SAECG) can detect imperceptible conduction abnormalities, and volume analysis using two-dimensional speckle-tracking echocardiography (2-DSTE) allows us to easily measure the phasic function of the left atrium (LA). Both conduction abnormalities and functional deformation of the LA may be linked to the clinical outcome; however, the exact relationship is unclear. The aim of this study was to investigate the relationship between the phasic function of the LA and electrical conduction using P-SAECG and 2-DSTE. The subjects were 112 male volunteers (age 46.9 ± 13.2 years) with normal cardiac function who underwent P-SAECG and 2-DSTE. The filtered p-wave duration (FPD) and the root-mean-square voltage for the last 20 ms (RMS20) on P-SAECG wave were measured in ms and µV, respectively. Total emptying function (EF) (reservoir function), passive EF (conduit function), and active EF (booster pump function) of the LA were calculated as percentages to evaluate phasic LA function using 2DSTE. The mean FPD was 134.3 ± 11.7 ms and the mean RMS20 was 4.59 ± 2.39 µV. The mean total EF was 60.5 ± 13.1%, mean passive EF was 39.4 ± 13.9%, and mean active EF was 35.1 ± 13.9%. FPD had a negative correlation with passive EF (r = - 0.20, p = 0.039). FPD showed no significant relationship with total EF (r = - 0.03, p = 0.78) or active EF (r = 0.13, p = 0.18). There was a significant association between RMS20 and passive EF (r = 0.19, p = 0.048); however, no there was no correlation between RMS20 and total EF (r = 0.12, p = 0.23), or between RMS20 and passive EF (r = - 0.02, p = 0.86). In multivariate regression analysis, passive EF was an independent factor that influenced FPD duration. This study indicated that FPD was associated with conduit function, which includes phasic LA function. Therefore, electrical conduction of the LA and left ventricular diastolic function are closely related. In the clinical setting, when conduction abnormalities are detected, lifestyle measures or interventions can be applied to reduce cardiovascular risk.

Long-Term Levocarnitine Ameliorates Left Ventricular Diastolic as Well as Systolic Dysfunction in Hemodialysis Patients　- Multi-Center Study.

Background: Levocarnitine has been reported to improve the left ventricular (LV) systolic function and decrease LV hypertrophy in hemodialysis (HD) patients. Its effect on LV diastolic dysfunction, however, has not yet been clarified. Methods and Results: HD patients (n=88) were given levocarnitine i.v. 1,000 mg for 12 months at the end of every dialysis session through the dialysis circuit of the venous site. LV ejection fraction (EF), E/A, E/e', left atrial volume index (LAVI) and LV mass index (LVMI) were measured before and 3, 6, 9, and 12 months after the start of levocarnitine on echocardiography. We regarded E/A≤0.8, E/e'>14 and LAVI>34 mL/m2 as LV diastolic dysfunction, and LVEF<55% as LV systolic dysfunction. We also investigated the effect of levocarnitine on HFpEF. Plasma brain natriuretic peptide, total carnitine, free carnitine, and acyl-carnitine and biochemistry parameters were measured. Levocarnitine significantly improved LV diastolic function in HD patients with LV diastolic dysfunction, but did not affect LV diastolic function in those with normal LV diastolic function. Levocarnitine significantly improved HFpEF. Levocarnitine significantly improved the LV systolic function in HD patients with LV systolic dysfunction but did not affect the LV systolic function in those with normal LV systolic function. Levocarnitine significantly decreased LVMI and increased plasma total, free, and acyl-carnitine. Conclusions: Levocarnitine ameliorates LV diastolic as well as LV systolic dysfunction in HD patients.

[Effect of the angiotensin II receptor antagonist (ARB), Irbesartan, on urinary markers in hypertensive patients].

PURPOSE: We examined the effect of the angiotensin II receptor antagonist (ARB), irbesartan (Irb), on urinary markers in hypertensive patients. SUBJECTS AND METHODS: We evaluated 87 patients in a 12-month prospective study: Group 1) 33 patients who were newly administered Irb (100 mg); Group 2) 33 patients who were switched to Irb ; and Group 3) 21 patients who did not undergo change to pre-existing Irb administration. Height, weight, systolic and diastolic blood pressure, clinical parameters, urine protein : creatinine ratio (UPC), and urinary markers (liver-type fatty acid binding protein (L-FABP), N-acetyl-ß-d-glucosaminidase, α1-microglobulin, and ß2-microglobulin) were measured at the baseline and at 12, 24, and 48 weeks. We examined changes in the clinical parameters, UPC, and urinary markers from the baseline. RESULTS: A tendency toward hypotension was observed in all groups (group newly administered Irb, group switched to Irb, and group without changes to Irb), but the difference was not statistically significant. Urinary L-FABP concentration (µg/g x Cr) decreased from 13.2 --> 8.9 and13.2 --> 10.2 at 24 and 48 weeks, respectively, after administration (p < 0.01) in the group newly administered Irb, from 19.5 --> 10.1 at 48 weeks after administration (p < 0.01) in the switched group, and from 9.6 --> 8.3, 8.1, and 6.2 (p < 0.01) in the group without changes to Irb. Changes in the Irb-administered groups were readily apparent. UPC decreased in the Irb-administered groups (p < 0.05), but there were no significant differences in the other urinary markers. Changes in urinary L-FABP and UPC were positively correlated in all cases of the Irb-administered groups (r = 0.25-0.57, p < 0.05), but were not positively correlated in the group without changes to Irb administration. The change in UPC was positively correlated with changes in systolic and diastolic blood pressure in all cases (r = 0.23-0.57, p < 0.05). CONCLUSION: It was concluded that the urinary L-FABP level, blood pressure, and UPC of hypertensive patients should be managed in daily practice using an ARB, including Irb.

Correlation between renal function and common risk factors for chronic kidney disease in a healthy middle-aged population: a prospective observational 2-year study.

BACKGROUND/AIMS: Age, proteinuria, metabolic syndrome, and hyperuricemia are the reported risk factors for chronic kidney disease (CKD) and cardiovascular disease (CVD). However, the best predictor of changes in renal function in the early stages of renal disease in a healthy middle-aged population is still unknown. Our study evaluated the correlation between changes in renal function and common risk factors to determine such a predictor. METHODS: In total, 2,853 healthy persons aged ≤50 years participated in the study. They had no proteinuria and were not on medications for hypertension, diabetes mellitus, hyperlipidemia, or hyperuricemia. Over 2 years, participants underwent annual health screening. The relationship between changes in estimated glomerular filtration rate (eGFR) and changes in risk factors for CKD was evaluated using univariate and multivariate linear regression analyses. RESULTS: Over 2 years, eGFR showed a significant decrease. Univariate regression analysis revealed that changes in fasting plasma glucose (FPG), total cholesterol, LDL-cholesterol, serum uric acid levels, and hemoglobin showed a significant negative correlation with changes in eGFR. Multiple regression analysis confirmed that changes in FPG, serum uric acid levels, in particular, and hemoglobin had a significant negative correlation with changes in eGFR. CONCLUSION: The changes in eGFR and other variables over 2 years were small and could be within expected biologic variation. A longer observational study is needed to elucidate whether FPG, serum uric acid and hemoglobin represent the earliest markers of eGFR decline.

Long-term effects of spironolactone in peritoneal dialysis patients.

ESRD treated with dialysis is associated with increased left ventricular hypertrophy, which, in turn, is related to high mortality. Mineralocorticoid receptor antagonists improve survival in patients with chronic heart failure; however, the effects in patients undergoing dialysis remain uncertain. We conducted a multicenter, open-label, prospective, randomized trial with 158 patients receiving angiotensin-converting enzyme inhibitor or angiotensin type 1 receptor antagonist and undergoing peritoneal dialysis with and without (control group) spironolactone for 2 years. As a primary endpoint, rate of change in left ventricular mass index assessed by echocardiography improved significantly at 6 (P=0.03), 18 (P=0.004), and 24 (P=0.01) months in patients taking spironolactone compared with the control group. Rate of change in left ventricular ejection fraction improved significantly at 24 weeks with spironolactone compared with nontreatment (P=0.02). The benefits of spironolactone were clear in patients with reduced residual renal function. As secondary endpoints, renal Kt/V and dialysate-to-plasma creatinine ratio did not differ significantly between groups during the observation period. No serious adverse effects, such as hyperkalemia, occurred. In this trial, spironolactone prevented cardiac hypertrophy and decreases in left ventricular ejection fraction in patients undergoing peritoneal dialysis, without significant adverse effects. Further studies, including those to determine relative effectiveness in women and men and to evaluate additional secondary endpoints, should confirm these data in a larger cohort.

Expression of prorenin receptor in renal biopsies from patients with IgA nephropathy.

Prorenin receptor (PRR) has been implicated in the onset and progression of various renal diseases, though its possible association with immunoglobulin A (IgA) nephropathy remains unclear. In the present study, we tried to clarify expression and pathophysiological significance of PRR in IgA nephropathy. We immunohistochemically assessed PRR levels in renal biopsy specimens from 48 patients with IgA nephropathy and evaluated its relevance to the clinical and pathological features of the disease. PRR was detected mainly in renal tubular cells, which was confirmed at the subcellular level using immunoelectron microscopy. The PRR-positive area (%PRR area) correlated with daily urinary protein, which is known to reflect disease severity (r=0.286, P=0.049). PRR levels were weaker in tubular cells bordering areas of severe interstitial fibrosis, where α-smooth muscle actin-positive myofibroblasts were present. We also used immunohistochemical detection of microtubule-associated protein-1 light chain 3 (LC3) and electron microscopy to assess autophagy, a cytoprotective mechanism downstream of PRR. We noted an apparent coincidence between autophagy activation in tubular cells and PRR expression in the same cells. Taken together, our findings suggest that renal expression of PRR in IgA nephropathy may be a compensatory response slowing disease progression by preventing tubular cell death and subsequent fibrosis through activation of cytoprotective autophagic machinery. Further studies using different type of kidney diseases could draw conclusion if the present finding is a generalized observation beyond IgA nephropathy.

Lanthanum carbonate for hyperphosphatemia in patients on peritoneal dialysis.

BACKGROUND: The efficacy of the phosphate binder lanthanum carbonate has been demonstrated for hemodialysis patients, but no studies have focused on patients undergoing continuous ambulatory peritoneal dialysis (CAPD). We evaluated whether lanthanum carbonate could control phosphate levels in patients on CAPD. ♢ METHODS: In this 48-week open-label prospective study, 28 patients on CAPD with a phosphate level of 6 mg/dL or greater were given lanthanum carbonate titrated from 750 mg to 2250 mg daily to achieve a target serum phosphate level of less than 6 mg/dL. The primary efficacy endpoint was reduction of serum phosphate to less than 6 mg/dL. Serum levels of calcium and parathyroid hormone were also evaluated, as were the Ca×P product and adverse effects. ♢ RESULTS: From week 4 to the end of the study at week 48, we observed a significant reduction of serum phosphate to 5.25 ± 0.97 mg/dL from 6.88 ± 1.06 mg/dL at study start (p < 0.01). At the end of the study, 78.6% of participants had achieved the target of less than 6 mg/dL. Because no change of serum calcium occurred, the Ca×P product declined significantly during the study. Intact parathyroid hormone declined gradually over the study period, but the change had not reached significance at the end of the study (p = 0.11). The mean final dose of lanthanum carbonate was 946 mg daily. The only adverse effect reported was mild nausea in 1 patient. ♢ CONCLUSIONS: Lanthanum carbonate is an effective phosphate binder that can control serum phosphate and Ca×P product in CAPD patients with hyperphosphatemia. Lanthanum carbonate was well tolerated in our population.

Adiponectin is increased and correlated with the degree of proteinuria, but plasma leptin is not changed in patients with chronic glomerulonephritis.

AIM: Altered regulation of adiponectin and leptin may be relevant to endothelial dysfunction and cardiovascular complications in patients with chronic glomerulonephritis. METHODS: The relationship between the levels of plasma adiponectin, leptin and proteinuria, glomerular filtration rate and metabolic risk factors was investigated in 38 patients with chronic glomerulonephritis. RESULTS: Plasma adiponectin was much higher in patients with heavy proteinuria (38.8 +/- 27.8 microg/mL) than in patients with mild proteinuria (13.3 +/- 5.1 microg/mL, P < 0.001) and with moderate proteinuria (18.1 +/- 8.0 microg/mL, P < 0.01). The levels of serum leptin were not changed among these groups. Proteinuria and lipoprotein(a) were a strong and direct correlate of plasma adiponectin (r = 0.75, P < 0.0001), while serum albumin and the glomerular filtration rate correlated inversely with this protein (r = -0.56, P = 0.0002; r = 0.38, P = 0.02). Body mass index and triglyceride were direct correlates (r = 0.37, P = 0.02 and r = 0.37, P = 0.02, respectively) of plasma leptin in patients with glomerulonephritis. CONCLUSIONS: Plasma adiponectin but not plasma leptin levels correlate with proteinuria in patients with chronic glomerulonephritis.

Dual blockade of the rennin-angiotensin system versus maximal recommended dose of angiotensin II receptor blockade in chronic glomerulonephritis.

BACKGROUND: Proteinuria and hypertension are predictors of poor renal outcome in chronic glomerulonephritis (CGN). At the same level of blood pressure (BP) control, we evaluated which is superior, dual blockade of the rennin-angiotensin system (RAS) with both angiotensin-converting enzyme inhibitor (ACEI) and angiotensin II type 1 (AT-1) receptor blockade (ARB) or single blockade of ARB to reduce proteinuria and to preserve renal function in patients with CGN. METHODS: In this prospective, parallel, open study of 86 patients with CGN, we compared the effects on proteinuria and renal functions of 36 months with comparable blood pressure (BP) control achieved by candesartan cilexetil (candesartan, 4-12 mg/day) or benazepril hydrochrolide (benazepril, 2.5-10 mg/day) with candesartan (4 mg/day). Aiming at BP 125/75 mmHg or less, the dose of candesartan (single blockade) or benazepril (dual blockade) was increased. RESULTS: Dual blockade decreased proteinuria more than single blockade with ARB (-42.3 vs. -60.5%, P < 0.01). Renal plasma flow (RPF) and glomerular filtration fraction (GFR) did not change significantly in either group. The filtration fraction (FF) decreased dual blockade more than single blockade (-1.7 vs. -19.0%, P < 0.05). Decreased FF was associated with the reduction of proteinuria (P < 0.05). Six percent of patients with dual blockade were not able to continue the study because of a dry cough. CONCLUSION: Long-term dual blockade decreased proteinuria more than single blockade with ARB. Although ARB and ACEI have a glomerular size-selective function for proteinuria, a greater antiproteinuric effect may depend on renal hemodynamics, especially FF. Increased levels of bradykinin after ACEI can decrease FF and ameliorate proteinuria. Dry cough is a significant adverse effect of ACE inhibitor.

Angiotensin receptor blockers and microalbuminuria in hypertensive patients with early (microalbuminuric) stage diabetic nephropathy.

Although protection of the kidneys by renin-angiotensin system (RAS) inhibitors is well known, differences in renal protection and the characteristics of RAS inhibitors have not been fully investigated. We randomly allocated 80 patients with hypertension complicated by type 2 diabetes and accompanied by microalbuminuria to 4 groups for treatment with the angiotensin receptor blockers (ARBs) telmisartan, losartan, candesartan and valsartan. Strict anti-hypertensive therapy was performed for 12 months (target blood pressure: lower than 130/80 mmHg), and renal function was compared. At study completion, all groups achieved the hypotensive target and no difference was noted in blood pressure levels. However, influences on renal function differed. In the telmisartan group in particular, the serum creatinine level was unchanged while the urinary albumin level and protein excretion were significantly decreased, displaying a strong renoprotective effect. These findings suggest that, although renal protection is a class effect of ARBs, the effect of telmisartan is particularly strong.

Renoprotective effect of the addition of losartan to ongoing treatment with an angiotensin converting enzyme inhibitor in type-2 diabetic patients with nephropathy.

Angiotensin converting enzyme inhibitors (ACE-Is) and angiotensin II receptor blockers (ARBs) are frequently used for the treatment for glomerulonephritis and diabetic nephropathy because of their albuminuria- or proteinuria-reducing effects. To many patients who are nonresponsive to monotherapy with these agents, combination therapy appears to be a good treatment option. In the present study, we examined the effects of the addition of an ARB (losartan) followed by titration upon addition and at 3 and 6 months (n=14) and the addition of an ACE-I followed by titration upon addition and at 3 and 6 months (n=20) to the drug regimen treatment protocol in type 2 diabetic patients with nephropathy for whom more than 3-month administration of an ACE-I or the combination of an ACE-I plus a conventional antihypertensive was ineffective to achieve a blood pressure (BP) of 130/80 mmHg and to reduce urinary albumin to <30 mg/day. During the 12-month treatment, addition of losartan or addition of an ACE-I to the treatment protocol reduced systolic blood pressure (SBP) by 10% and 12%, diastolic blood pressure (DBP) by 7% and 4%, and urinary albumin excretion by 38% and 20% of the baseline value, respectively. However, the effects on both BP and urinary albumin were not significantly different between the two therapies. In conclusion, addition of losartan or an ACE-I to an ongoing treatment with an ACE-I, or addition of an ACE-I to ongoing treatment with a conventional antihypertensive were equally effective at reducing the urinary albumin excretion and BP, and provided renal protection in patients with type-2 diabetic nephropathy.

Hepatocyte growth factor gene therapy slows down the progression of diabetic nephropathy in db/db mice.

BACKGROUND: Effect of hepatocyte growth factor (HGF) has scarcely been determined on diabetic nephropathy. METHODS: Adenovirus encoding human HGF gene or LacZ gene (as the control) was injected into the hindlimb muscles of the C57BL/KsJ-db/db (db/db) mice at the age of 12 weeks, a model of genetic diabetes. Diabetic nephropathy was then evaluated at the age of 24 weeks. RESULTS: The urine volume and albumin excretion progressively decreased in the control, whereas they remained unchanged in the HGF-treated group during the 12-week follow-up. The HGF gene therapy did not affect glucose metabolism. However, it resulted in a better renal function as evaluated by creatinine clearance (Ccr) than the control; Ccr was progressively worsened in controls (0.14 +/- 0.02 liters/day) whereas unchanged in the HGF gene-treated group (0.38 +/- 0.09 liters/day, p < 0.05). Kidneys of the HGF gene-treated mice showed glomeruli with greater area and cell population, smaller glomerular sclerotic index, and less fibrosis in both glomeruli and renal tubules, where apoptotic rate of glomerular endothelial cells and that of tubular epithelial cells were significantly decreased. TGF-beta1 expression was significantly decreased in kidneys of the HGF gene-treated group. Finally, the HGF treatment significantly improved the long-term survival of db/db mice. CONCLUSIONS: The HGF gene delivery thus appeared to slow down the aggravation of diabetic nephropathy in db/db mice by attenuating progression from the hyperfiltration phase into the sclerotic phase through antiapoptotic and antifibrotic actions. The present findings suggest that the HGF gene delivery can be a novel therapeutic approach against diabetic nephropathy.

[Cardiac diagnostic techniques in dialysis patients].

The field of cardiovascular disease in patients with dialysis has seen a tremendous increase in the number and diversity of diagnostic techniques available. Therefore, the newer methods have added new types of information to our diagnostic area. The plain chest roentgenogram and electrocardiogram are still simple and important tests. The other noninvasive procedures such as echocardiography, radionuclide techniques, CT and MRI supply important additional information concerning cardiac anatomy and function, but invasive cardiac catheterization remains the only method for accurately measuring intracardiac pressures and cineangiography is still necessary for defining the anatomy of the coronary arteries. Recently, the determination of natriuretic peptides (ANP,BNP), noradrenaline and troponin is added to evaluate cardiac function. The purpose of this paper discusses the use of these techniques in patients with dialysis.

Involvement of apoptosis in patients with diabetic nephropathy: A study on plasma soluble Fas levels and pathological findings.

AIMS: We investigated the relationship between levels of plasma soluble Fas (sFas) and stages of diabetic nephropathy, with special reference to apoptosis and clinical features of diabetic nephropathy in 168 patients with diabetic nephropathy. RESULTS: There was a positive correlation between plasma sFas and creatinine levels, between sFas levels and urinary protein levels, and between sFas levels and urinary albumin. There was a negative correlation between plasma sFas levels and creatinine clearance. Plasma sFas levels in the early stage (stages 1, 2, 3A) and advanced stage (stages 3B and 4) were 2.6 +/- 0.1 and 5.4 +/- 0.5 ng/mL, respectively. Plasma sFas level of the advanced stage was significantly higher than that of the early stage. The number of proliferating cell nuclear antigen (PCNA) positive cells was significantly lower in the advanced stage than in the early stage. The number of in situ nick-end labelling (TUNEL) positive cells was also significantly lower in the advanced stage than in the early stage, suggesting the suppression of apoptosis. CONCLUSION: These data suggest that apoptosis is involved in the advancement of diabetic nephropathy, and that plasma sFas level might be a predicting factor for prognosis.

C-reactive protein, lipoprotein(a), homocysteine, and male sex contribute to carotid atherosclerosis in peritoneal dialysis patients.

BACKGROUND: In patients with end-stage renal disease, the morbidity and mortality of cardiovascular disease are substantially greater than in the general population. Advancement in understanding the pathogenesis of atherosclerotic vascular disease suggests a central role of inflammation in atherogenesis. However, clinical data evaluating the role of inflammation in atherogenesis are sparse in peritoneal dialysis (PD) patients. METHODS: We measured serum C-reactive protein (CRP), intact parathyroid hormone, lipoprotein(a) [Lp(a)], interleukin-1 receptor antagonist (IL-1Ra), tumor necrosis factor soluble receptor (TNF-sR), fibrinogen, and plasma homocysteine (Hcy), as well as intima-media thickness (IMT) and number of atherosclerotic plaques (plaque score [PS]) in the carotid arteries by means of carotid B-mode ultrasonography in 59 PD patients (35 men, 24 women; mean age, 52.4 years; average dialysis period, 36 months). All patients had chronic glomerulonephritis. RESULTS: Sixty-eight percent of PD patients had at least 1 plaque. Serum CRP level was greater than the upper limit of the normal range in 52.5% of patients. Compared with PD patients with normal CRP levels, concentrations of such proinflammatory cytokines as IL-1Ra and TNF-sR, Lp(a), and Hcy were increased in PD patients with elevated CRP levels. However, no differences in plasma fibrinogen and intact parathyroid hormone levels were found between PD patients with increased and normal CRP levels. In a multiple regression model, age, male sex, CRP level, and Lp(a) level were independent predictors of IMT. Similarly, male sex, CRP level, Lp(a) level, and Hcy level were independent correlates of PS. CONCLUSION: This study suggests that Lp(a) and Hcy levels and male sex, and especially CRP level, have an important role in carotid atherosclerosis in PD patients.