Klotho Supplementation Reverses Renal Dysfunction and Interstitial Fibrosis in Remnant Kidney.

INTRODUCTION: While recent investigations show that klotho exerts renoprotective actions, it has not been fully addressed whether klotho protein supplementation reverses renal damage. METHODS: The impacts of subcutaneous klotho supplementation on rats with subtotal nephrectomy were examined. Animals were divided into 3 groups: group 1 (short remnant [SR]): remnant kidney for 4 weeks, group 2 (long remnant [LR]): remnant kidney for 12 weeks, and group 3 (klotho supplementation [KL]): klotho protein (20 µg/kg/day) supplementation on the remnant kidney. Blood pressure, blood and urine compositions with conventional methods such as enzyme-linked immunosorbent assay and radioimmunoassay, kidney histology, and renal expressions of various genes were analyzed. In vitro studies were also performed to support in vivo findings. RESULTS: Klotho protein supplementation decreased albuminuria (-43%), systolic blood pressure (-16%), fibroblast growth factor (FGF) 23 (-51%) and serum phosphate levels (-19%), renal angiotensin II concentration (-43%), fibrosis index (-70%), renal expressions of collagen I (-55%), and transforming growth factor ß (-59%) (p < 0.05 for all). Klotho supplementation enhanced fractional excretion of phosphate (+45%), glomerular filtration rate (+76%), renal expressions of klotho (+148%), superoxide dismutase (+124%), and bone morphogenetic protein (BMP) 7 (+174%) (p < 0.05 for all). CONCLUSION: Our data indicated that klotho protein supplementation inactivated renal renin-angiotensin system, reducing blood pressure and albuminuria in remnant kidney. Furthermore, exogenous klotho protein supplementation elevated endogenous klotho expression to increase phosphate excretion with resultant reductions in FGF23 and serum phosphate. Finally, klotho supplementation reversed renal dysfunction and fibrosis in association with improved BMP7 in remnant kidney.

In vitro study on effect of bardoxolone methyl on cisplatin-induced cellular senescence in human proximal tubular cells.

Bardoxolone methyl [methyl-2-cyano-3, 12-dioxooleana-1, 9(11)dien-28-oate (CDDO-Me)], an activator of the nuclear factor erythroid-derived 2-related factor2 pathway, is a potential therapeutic candidate for the treatment of kidney diseases. However, its effect against cellular senescence remains unclear. This study aimed to investigate whether CDDO-Me protects cells against cisplatin-induced cellular senescence using an in vitro model. The human renal proximal tubular epithelial cell line HK-2 was treated with cisplatin for 6 h, followed by treatment with or without CDDO-Me (0.1 or 0.2 µmol/L). Senescence markers were analyzed using western blotting and real-time PCR. Apoptosis was evaluated through TUNEL staining. Cisplatin induced changes in the levels of markers specific for proliferation, cell cycle, and senescence in a time- and dose-dependent manner. Furthermore, IL-6 and IL-8 levels in the culture medium increased markedly. These data suggested that cellular senescence-like alterations occurred in HK-2 cells exposed to cisplatin. CDDO-Me treatment reversed the cisplatin-mediated alterations in the levels of cellular senescence markers. The antioxidant enzymes, HO1, NQO1, GPX1, and CAT were upregulated by CDDO-Me treatment. Furthermore, CDDO-Me treatment induced apoptosis in cisplatin-exposed HK-2 cells. Pretreatment with Ac-DEVD-CHO, the caspase inhibitor, suppressed the reversal effect of CDDO-Me against cisplatin-induced cellular senescence-like alterations. This study showed that CDDO-Me attenuated cisplatin-induced premature senescence of HK-2 cells. This beneficial effect may be related to Nrf2 activation. Our findings also showed that CDDO-Me induced apoptosis in cisplatin-treated HK-2 cells, potentially protecting the kidneys from cellular senescence. CDDO-Me appears to be a candidate treatment for acute kidney injury.

Central and brachial pulse pressure predicts cardiovascular and renal events in treated hypertensive patients.

PURPOSES: Central blood pressure is a stronger predictor of cardiovascular prognosis rather than brachial blood pressure. The reflection wave reaches the abdominal aorta sooner than ascending aorta. Thus, the contribution of central pulse pressure (cPP) to renal events may differ from that of cardiovascular events. METHODS: The subanalysis of the ABC-J II study was performed. Subjects were 3434 treated hypertensive patients with a mean follow-up of 4.7 years. Left ventricular hypertrophy, an index of cardiovascular risk, correlated with cPP better than central systolic blood pressure in this cohort. The contribution of brachial pulse pressure (bPP) and cPP to cardiovascular and renal events was analysed. RESULTS: Cox proportional-hazard analysis revealed that sex (p < 0.001), height (p < 0.05), history of cardiovascular diseases (p < 0.001), number of antihypertensive drugs (p < 0.05), and cPP (p < 0.05) contributed to cardiovascular events. However, Cox proportional-hazard analysis disclosed that baseline serum creatinine (p < 0.001) and bPP (p < 0.05) predicted renal events. After adjusting for the history of cardiovascular diseases, Cox regression demonstrated only sex as a significant predictor of cardiovascular events. After adjusting for baseline serum creatinine, no parameters were shown to predict renal events. CONCLUSIONS: The present findings support our previous data that the absence of cardiovascular or renal diseases is an important determinant for event-free survival, and suggest that cPP and bPP contribute to cardiovascular and renal events in treated hypertensive patients.

Klotho supplementation ameliorates blood pressure and renal function in DBA/2-pcy mice, a model of polycystic kidney disease.

Klotho interacts with various membrane proteins such as receptors for transforming growth factor-ß (TGF-ß) and insulin-like growth factor (IGF). Renal expression of klotho is diminished in polycystic kidney disease (PKD). In the present study, the effects of klotho supplementation on PKD were assessed. Recombinant human klotho protein (10 µg·kg-1·day-1) or a vehicle was administered daily by subcutaneous injection to 6-wk-old mice with PKD (DBA/2-pcy). Blood pressure was measured using tail-cuff methods. After 2 mo, mice were killed, and the kidneys were harvested for analysis. Exogenous klotho protein supplementation reduced kidney weight, cystic area, systolic blood pressure, renal angiotensin II levels, and 8-epi-PGF2α excretion (P < 0.05). Klotho protein supplementation enhanced glomerular filtration rate, renal expression of superoxide dismutase, and klotho itself (P < 0.05). Klotho supplementation attenuated renal expressions of TGF-ß and collagen type I and diminished renal abundance of Twist, phosphorylated Akt, and mammalian target of rapamycin (P < 0.05). Pathological examination revealed that klotho decreased the fibrosis index and nuclear staining of Smad in PKD kidneys (P < 0.05). Our data indicate that klotho protein supplementation ameliorates the renin-angiotensin system, reducing blood pressure in PKD mice. Furthermore, the present results implicate klotho supplementation in the suppression of Akt/mammalian target of rapamycin signaling, slowing cystic expansion. Finally, our findings suggest that klotho protein supplementation attenuated fibrosis at least partly by inhibiting epithelial mesenchymal transition in PKD.

Inferred systolic blood pressure levels to switch from lifestyle modifications to antihypertensive medications: a success-rate oriented simulation.

Objective: This simulation study attempted to infer the systolic blood pressure (SBP) levels at which subjects with hypertension, health nurses, and primary physicians should switch their preference of their treatment policies from lifestyle modifications to antihypertensive medications in virtual Japanese sample populations. Methods: We assumed that SBP levels were normally distributed and that the incidence rate of cardiovascular disease (IRCVD, events/year) increased exponentially according to SBP. The total IRCVD was calculated by the definite integral for the product of the distribution of SBP multiplied by IRCVD at each SBP level. The success rates were calculated according to SBP and metabolic risk profiles in the two approaches, respectively. We deduced the hypothetical SBP levels by solving differential equations of ∆(IRCVD)/ ∆(SBP) = 0 using numerical analysis. Results: In the realistic situations where the subjects were not affirmative to antihypertensive medications, the inferred SBP level to switch from lifestyle modifications to antihypertensive medications should be around 150 mmHg. If the subjects are affirmative to antihypertensive medications, the SBP level should be lowered to 140 mm Hg. Conclusion: This success rate-oriented simulation proposes that the SBP level to switch from lifestyle modifications to antihypertensive medications can be modulated according to the behavioral propensity for taking antihypertensive medications.Abbreviations: The following abbreviations are used in this manuscript: CVD: cardiovascular disease; LM: lifestyle modifications; AM: antihypertensive medications; IRCVD: incidence rate of cardiovascular disease (events/year); SBP: systolic blood pressure; ∆IRCVD: the improvements in the incidence rate of cardiovascular disease by lifestyle modifications and/or by antihypertensive medications.

Oxidative stress increases megalin expression in the renal proximal tubules during the normoalbuminuric stage of diabetes mellitus.

Megalin, an endocytic receptor expressed in proximal tubule cells, plays a critical role in renal tubular protein reabsorption and is associated with the albuminuria observed in diabetic nephropathy. We have previously reported increased oxidant production in the renal cortex during the normoalbuminuric stage of diabetes mellitus (DM); however, the relationship between oxidative stress and renal megalin expression during the normoalbuminuric stage of DM remains unclear. In the present study, we evaluated whether oxidative stress affects megalin expression in the normoalbuminuric stage of DM in a streptozotocin-induced diabetic rat model and in immortalized human proximal tubular cells (HK-2). We demonstrated that increased expression of renal megalin accompanies oxidative stress during the early stage of DM, before albuminuria development. Telmisartan treatment prevented the diabetes-induced elevation in megalin level, possibly through an oxidative stress-dependent mechanism. In HK-2 cells, hydrogen peroxide significantly increased megalin levels in a dose- and time-dependent manner; however, the elevation in megalin expression was decreased following prolonged exposure to severe oxidative stress induced by 0.4 mmol/l hydrogen peroxide. High-glucose treatment also significantly increased megalin expression in HK-2 cells. Concurrent administration of the antioxidant N-acetyl-cysteine blocked the effects of high glucose on megalin expression. Furthermore, the hydrogen peroxide-induced increase in megalin expression was blocked by treatment with phosphatidylinositol 3-kinase and Akt inhibitors. Increase of phosphorylated Akt expression was also seen in the renal cortex of diabetic rats. Taken together, our results indicate that mild oxidative stress increases renal megalin expression through the phosphatidylinositol 3-kinase-Akt pathway in the normoalbuminuric stage of DM.

Klotho suppresses the renin-angiotensin system in adriamycin nephropathy.

BACKGROUNDS: Klotho protein interacts with the transforming growth factor ß (TGF-ß) receptor and Wnt, which contribute to the progression of renal disease, inhibiting their signals. Renal and circulating klotho levels are diminished in chronic kidney disease. METHODS: Experiments were performed to assess whether supplementation of klotho protein could have protective effects on the kidney. Rats were injected with adriamycin (5 mg/kg) and divided into three groups: those treated with vehicle, those treated with klotho protein and those treated with klotho plus 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD). Rats without adriamycin treatment were used as a control. RESULTS: Adriamycin reduced the serum klotho concentration and renal expression of klotho and E-cadherin. Adriamycin also increased the renal expression of Wnt, TGF-ß, and angiotensinogen, as well as the renal abundance of ß-catenin and angiotensin II. Klotho supplementation suppressed adriamycin-induced elevations of ß-catenin and angiotensin II with sustained Wnt expression. Combined treatment with klotho and TDZD reversed the klotho-induced improvements in the renal abundance of ß-catenin and angiotensin II as well as the expression of TGF-ß and angiotensinogen without affecting E-cadherin. CONCLUSIONS: Our data indicate that Wnt is involved in the pathogenesis of adriamycin nephropathy. Furthermore, klotho supplementation inhibited Wnt signaling, ameliorating renal angiotensin II. Finally, klotho protein appears to suppress epithelial-mesenchymal transition by inhibiting TGF-ß and Wnt signaling.

Kidney resistive index relates to variations of home blood pressure in chronic kidney diseases.

BACKGROUND: Kidney resistive index (RI) correlates with tubulointerstitial changes and predicts renal prognosis. Most patients with chronic kidney diseases (CKDs) manifest high blood pressure and atherosclerotic cardiovascular diseases. In addition, various atherosclerotic indexes relate to variations in blood pressure. METHODS: Subjects were 70 CKD patients, who visited our office and agreed to measure home blood pressure and receive renal ultrasonography. Cross-sectional analyses were performed. RESULTS: Patient age was averaged 61 ± 15 (SD) y/o and 60% were male. Mean serum creatinine and proteinuria were 1.2 ± 0.5 mg/dl and 0.2 ± 0.5 g/gCr, respectively. Office blood pressure and kidney RI were 128 ± 17/75 ± 11 mmHg and 0.66 ± 0.08, respectively. Multivariate regression analysis revealed that age and office blood pressure independently correlated to kidney RI (p < 0.05 for each). Home blood pressure was averaged 122 ± 7/70 ± 6 mmHg. Both standard deviation and the maximal-minimal difference in home systolic blood pressure related to kidney RI (p < 0.05). CONCLUSIONS: The present results indicate that office blood pressure correlates to kidney RI, which predicts renal prognosis. In addition, our data implicate that kidney RI relates to variations in home systolic blood pressure, and suggest that kidney RI may be a good index for atherosclerosis in CKD patients.

Antialbuminuric actions of calcilytics in the remnant kidney.

Hyperphosphatemia accelerates the progression of chronic kidney diseases. In the present study, the effects of ronacaleret, a calcilytic agent, on renal injury were assessed in the following four groups of rats: 5/6-nephrectomized Wistar rats as a control (C group), rats treated with ronacaleret (3 mg·kg(-1)·day(-1); R group), rats treated with calcitriol (30 ng·kg(-1)·day(-1); V group), and rats treated with both ronacaleret and calcitriol (R + V group). Three months later, rats were euthanized under anesthesia, and the remnant kidneys were harvested for analysis. Albuminuria was lower in the R and V groups than in the C group (P < 0.05). Creatinine clearance was elevated in the R and V groups compared with the C group (P < 0.05). Serum Ca(2+) and renal ANG II were higher in the R + V group than in the C group (P < 0.05 for each), and serum phosphate was reduced in the R group compared with the C group (P < 0.05). Fibroblast growth factor-23 was lower in the R group and higher in the V and R + V groups than in the C group. However, parathyroid hormone did not differ significantly among the four groups. Renal klotho expression was elevated in the R and V groups compared with the C group (P < 0.05). The present data indicate that ronacaleret preserves klotho expression and renal function with reductions in serum phosphate and albuminuria in 5/6-nephrectomized rats. Our findings demonstrate that vitamin D prevents declines in klotho expression and renal function, suppressing albuminuria.

The contribution of epithelial-mesenchymal transition to renal fibrosis differs among kidney disease models.

The impact of the epithelial-mesenchymal transition (EMT) to the formation of renal fibrosis has been debated in several lineage-tracing studies, with conflicting findings. Such disparities may have arisen from varying experimental conditions such as different disease models, the mouse strain, and type of genetic alteration used. In order to determine the contribution of these factors to EMT, we generated four kidney disease models in several mouse strains genetically modified to express enhanced green fluorescence protein (EGFP) in cortical tubular epithelial cells under the control of the γ-glutamyl transpeptidase promoter. Using this approach, the EMT was visible and quantifiable based on a count of EGFP-positive interstitial cells in the fibrotic kidney sections of the four renal disease models found to be either EMT-prone or -resistant. The EMT-prone models consisted of unilateral ureteral obstruction and ischemic nephropathy in SJL mice. The EMT-resistant models consisted of ureteral obstruction in C57B/6 and F1(C57B/6 × SJL) mice, adriamycin nephrosis in 129 mice, and nephrotoxic serum nephritis in SJL mice. Analyses of these renal disease models suggest the emergence of EMT-derived fibroblasts arises in a disease-specific and strain-dependent manner. Thus, when considering molecular mechanisms and involvement of the EMT in renal fibrosis, it is important to take into account the experimental conditions, particularly the mouse strain and type of disease model.

Calcitriol supplementation improves endothelium-dependent vasodilation in rat hypertensive renal injury.

BACKGROUND/AIMS: Vitamin D increases renal expression of klotho in normotensive rats. Klotho reduces oxidative stress. METHODS: In this study, we aimed to determine if vitamin D would suppress oxidative stress using 4 groups of hypertensive rats: uninephrectomized, stroke-prone, spontaneously hypertensive rats fed a high-salt (6%) diet (controls; C); those treated with irbesartan (I); those treated with calcitriol (V); and those treated with both irbesartan and calcitriol (I+V). RESULTS: Systolic blood pressure was higher in the C group than in the I and I+V groups. Albuminuria was attenuated in groups I, V, and I+V. Renal angiotensin II (AngII) concentration was lower in groups I and I+V than in group C, and plasma AngII levels of groups I and V were higher and lower than those in group C, respectively. Compared with group C, renal klotho expression, 8-epi-prostaglandin F2α excretion, and acetylcholine-induced decrease in blood pressure improved in the V and I+V groups. CONCLUSIONS: The data indicate that irbesartan effectively decreases blood pressure and renal AngII levels, and improves albuminuria. Our findings indicate that vitamin D enhances klotho expression, suppressing oxidative stress and albuminuria without substantial changes in renal AngII levels. These results suggest that the amelioration of endothelium function by vitamin D involves free klotho.

Calcium channel blockers suppress daily variations of blood pressure in hypertensive patients with end-stage renal diseases.

Hypertension is a well-known cardiovascular risk. Patients with end-stage renal diseases frequently suffer hypertension. Furthermore, daily variations of blood pressure are relatively large in patients treated with hemodialysis, partly due to ultrafiltration. Twenty hypertensive patients with end-stage renal diseases whose blood pressure was controlled by a single antihypertensive agent, either angiotensin receptor antagonist (ARB) or calcium channel blocker (CCB), were enrolled into the study. Home blood pressure measurements were also performed. Average systolic and diastolic blood pressures were similar between two agents. However, variations of systolic blood pressure during ARB treatment were greater than those of CCB, and maximal differences in daily systolic blood pressure during treatment with ARB (19±7 mmHg) were greater than those with CCB (14±6 mmHg, p<0.01). Systolic blood pressure measured after hemodialysis under ARB therapy (110±6 mmHg) was lower than that of CCB (118±6 mmHg, p<0.05). Daily variations of diastolic blood pressure were similar between ARB and CCB periods. Our results indicate that variations of systolic blood pressure during ARB treatment are larger than CCB, and suggest that CCB is useful to obtain the better quality of blood pressure control, improving blood pressure stability by preventing substantial drops in blood pressure in hypertensive patients with end-stage renal diseases.

Long-term survival benefits of combined hemodialysis and peritoneal dialysis.

Recently, it was reported that concomitant hemodialysis (HD) in peritoneal dialysis (PD) patients facilitated continuation of PD treatment and mitigated the deterioration of peritoneal function in patients with uremic symptoms and excess body fluid associated with loss of residual renal function. To determine the effect of combined HD and PD on patient and technique survival, we undertook a retrospective cohort study of patients who underwent PD at Saitama Medical University Hospital between 1995 and 2010. We compared patients who started PD during 1995 2002 with those who started during 2003- 2010. Because our center started a new strategy of supplementing PD with once-weekly HD in 2000, the effects of combination therapy could be determined by comparing the data obtained during the two periods. The 440 patients (274 men, 166 women) who started PD during the study period had a mean age of 60.2 +/- 73 years. The mean age was significantly higher in the 2003 - 2010 group than in the 1995 - 2002 group. Using a Kaplan-Meier plot, we observed a significant difference in technique survival (p < 0.001). The technique survival rate at 3 and 5 years was, respectively, 89% and 74% in the 2003-2010 group and 68% and 35% in the 1995 - 2002 group (p < 0.05). Cumulative patient survival at 3 and 5 years was, respectively, 87% and 72% in the 2003 - 2010 group and 69% and 51% in the 1995 - 2003 group (p < 0.01). Patient and technique survival were significantly improved in PD patients receiving the combination of HD and PD.

Fibroblast growth factor 23 enhances renal klotho abundance.

Klotho constitutes the receptor for fibroblast growth factor 23 (FGF23). However, the effects of FGF23 on renal and circulating klotho are not well-known. In vivo experiments were performed to assess the effects of FGF23 (10 µg/kg), parathyroid hormone (PTH, 10 µg/kg), and 1,25-dihydroxy-vitamin D3 (1,25VD, 1 µg/kg) on renal expression and serum concentration of klotho in Wistar rats. Phosphate excretion was increased at 3 h after FGF23 administration (p < 0.05). Renal klotho expressions and serum klotho levels were elevated at 3 h (p < 0.01) by FGF23. At 24 h, phosphate excretion was still elevated (p < 0.05), and serum phosphate, 1,25VD, and PTH were reduced (p < 0.05). However, serum and renal klotho returned to the control level at 24 h. PTH markedly increased phosphate excretion after 24 h (p < 0.01). There were increases in FGF23 at 3 and 24 h, and 1,25VD at 24 h after PTH administration (p < 0.05). Serum klotho concentration and renal klotho expression were elevated by PTH at 3 or 24 h. After 24 h of exposure to 1,25VD, considerable increases in serum FGF23, calcium, and phosphate were seen (p < 0.05), but PTH was decreased (p < 0.01). 1,25 VD elevated renal klotho expression and serum klotho (p < 0.05) at 3 h, but returned to control levels at 24 h. Our data indicate that FGF23 rapidly increases renal klotho expression and serum klotho. The present findings are consistent with the notion that PTH increases phosphate excretion at least in part through elevations of FGF23 and klotho. Moreover, our results suggest that 1,25VD increases klotho expression independently of FGF23.

Angiotensin-converting enzyme inhibition curbs tyrosine nitration of mitochondrial proteins in the renal cortex during the early stage of diabetes mellitus in rats.

Experiments were performed to evaluate the hypothesis that ACE (angiotensin-converting enzyme) inhibition (enalapril) suppresses 3-NT (3-nitrotyrosine) production in the renal cortex during the early stage of Type 1 DM (diabetes mellitus) in the rat. Enalapril was administered chronically for 2 weeks to subsets of STZ (streptozotocin)-induced DM and vehicle-treated sham rats. O(2)(-) (superoxide anion) and NO(x) (nitrate+nitrite) levels were measured in the media bathing renal cortical slices after 90 min incubation in vitro. SOD (superoxide dismutase) activity and 3-NT content were measured in the renal cortex homogenate. Renal cortical nitrated protein was identified by proteomic analysis. Renal cortical production of O(2)(-) and 3-NT was increased in DM rats; however, enalapril suppressed these changes. DM rats also exhibited elevated renal cortical NO(x) production and SOD activity, and these changes were magnified by enalapril treatment. 2-DE (two-dimensional gel electrophoresis)-based Western blotting revealed more than 20 spots with positive 3-NT immunoreactivity in the renal cortex of DM rats. Enalapril treatment blunted the DM-induced increase in tyrosine nitration of three proteins ACO2, GDH1 and MMSDH (aconitase 2, glutamate dehydrogenase 1 and methylmalonate-semialdehyde dehydrogenase), each of which resides in mitochondria. These data are consistent with enalapril preventing DM-induced tyrosine nitration of mitochondrial proteins by a mechanism involving suppression of oxidant production and enhancement of antioxidant capacity, including SOD activation.

Various approaches for vascular health in elderly women.

Cardiovascular disease is one of the leading causes of morbidity and mortality in elderly women. Several previous studies evaluated various cardiovascular risk factors, such as brachial blood pressure (BP), systolic blood pressure (SBP), pulse pressure (PP), pulse wave velocity (PWV), central aortic pressure (CAP), and so on. More recently, measurement of ambulatory blood pressure (AMBP) was shown to be superior to clinic measurements in predicting cardiovascular mortality. However, the data are limited concerning the relationship among these variables in elderly women. In the present study, the data for clinic BP including PP, PWV, CAP, and AMSBP and AMCAP obtained using BPro were evaluated in 24 elderly hypertensive women. Although there was a significant correlation between AMSBP and AMCAP, no correlations were found between repeated measured values and values measured in the clinic on one occasion. In conclusion, measuring PWV and CAP in the clinic in patients with white coat hypertension or masked hypertension may not be an accurate way to measure these parameters.

Aliskiren reduces morning blood pressure in hypertensive patients with diabetic nephropathy on hemodialysis.

Our previous study indicated that the exchange from an angiotensin receptor blocker (ARB) to aliskiren reduced morning blood pressure and albuminuria in hypertensive patients with diabetic nephropathy. We extended the above study and assessed the effects of exchanging from an ARB to aliskiren on home blood pressure in hypertensive patients with diabetic nephropathy on chronic hemodialysis. The patients who were persistently hypertensive despite antihypertensive therapy, including ARB, were considered as candidates for the exchange from the ARB to aliskiren. Patients' age and durations of diabetes and hemodialysis were averaged as 62 ± 9 years old, 15 ± 8 and 7 ± 3 years, respectively. Aliskiren decreased morning systolic blood pressure (149 ± 14 to 144 ± 13 mm Hg, n = 30, P < .01) and plasma renin activity (3.5 ± 1.1 to 1.2 ± 0.6 ng/mL/h, P < .01) without changes in serum potassium. Aliskiren also reduced interdialytic weight gain (2.7 ± 0.6 to 2.5 ± 0.5 kg/interval, P < .05) and attenuated the magnitude of intradialytic declines in systolic (-20 ± 11 to -17 ± 10 mm Hg, P < .05) and diastolic blood pressure (-9 ± 6 to -5 ± 5 mm Hg, P < .01). The exchange from an ARB to aliskiren is safe and useful to control home blood pressure in hypertensive hemodialysis patients with diabetic nephropathy. Aliskiren reduced both intradialytic blood pressure drops and interdialytic weight gain in patients with DN.

Elucidating mechanisms underlying altered renal autoregulation in diabetes.

Previous studies have reported that high-salt intake paradoxically activates tubuloglomerular feedback (TGF) in type 1 diabetes. Using Zucker lean (ZL) and diabetic fatty (ZDF) rats on normal and high-salt diets, renal hemodynamics and the renin-angiotensin system (RAS) were characterized. On normal salt diet, glomerular filtration rate (GFR) was higher in ZDF than ZL rats. Autoregulation of GFR was less efficient and lithium clearance was lower in ZDF rats than ZL rats. Salt load reduced GFR in ZDF rats with restoration of lithium clearance and partial improvement in autoregulatory index (AI). The administration of 8-cyclopentyl-1,3-dipropylxanthine, a selective adenosine-1 receptor antagonist to ZDF rats on a high-salt diet abolished the improvement of AI in GFR. However, this effect was seen by neither (Cx40)GAP27 nor (Cx37,43)GAP27, which inhibits connexin (Cx) 40 or Cx37. Renal ANG II was higher in ZDF than ZL rats on normal salt diet, but the difference was eliminated by a salt load. The present data provide the first demonstration for a salt paradox in type 2 diabetes and implicate that in addition to Cx alterations, an enhanced proximal reabsorption attenuates TGF, underlying glomerular hyperfiltration and RAS activation. These data suggest that a high-salt diet standardizes distal delivery in diabetes, suppressing the RAS, and improving GFR autoregulation and hyperfiltration through adenosine.

Long-term effects of calcium antagonists on augmentation index in hypertensive patients with chronic kidney disease: a randomized controlled study.

BACKGROUND: Our previous retrospective study showed that benidipine was superior to amlodipine (AM) for reducing proteinuria and preserving the augmentation index (AI) in patients with chronic kidney disease (CKD). METHODS: The present study enrolled CKD patients whose blood pressure was not well controlled by an angiotensin receptor blocker (ARB) and a calcium channel blocker other than AM or azelnidipine (AZ). Either AM (5 mg) or AZ (16 mg) was prescribed randomly. Clinical parameters, including proteinuria, serum creatinine, and AI, were measured before initiation of AM or AZ and 1 year later to assess the long-term effect on renal function and central blood pressure. RESULTS: Brachial and central blood pressures were similarly reduced in both groups. However, pulse rate increased in the AM group, but decreased in the AZ group (+3 ± 1 vs. -2 ± 1 bpm, p < 0.0001). The reduction of proteinuria was greater in the AZ group (-29 ± 2 vs. -38 ± 3%, p < 0.01). Improvement of AI adjusted for a pulse rate of 75 bpm was larger in the AZ group than in the AM group (-4 ± 1 vs. -9 ± 1%, p < 0.05). In both groups, estimated GFR remained unchanged throughout the observation period. CONCLUSION: In hypertensive patients with CKD, combined treatment with AZ and an ARB decreases proteinuria and preferentially improves arterial reflection.