糖尿病大鼠肾小管上皮细胞-肌成纤维细胞转分化及氯沙坦对其的影响

【目的】观察糖尿病大鼠肾小管上皮细胞-肌成纤维细胞转分化(TEMT)及氯沙坦干预对其的影响。【方法】雄性Wistar大鼠随机分为正常对照组和糖尿病模型组;后者经STZ诱导糖尿病模型成功后再随机分为糖尿病组和氯沙坦干预组[氯沙坦20mg/(kg·d)]。分别于第8周和第16周时每组各处死5只大鼠。测定24h尿蛋白排泄量、血肌酐;留取肾组织作HE和Masson染色,观察肾小管间质损伤指数、肾间质胶原面积;免疫组织化学法检测肾小管上皮细胞α-平滑肌肌动蛋白(α-SMA)、波形蛋白(Vimentin)和转化生长因子-β1(TGF-β1)表达,并作半定量分析。【结果】①与对照组相比,糖尿病模型组大鼠肾小管间质损伤指数和肾间质胶原面积明显增加(P<0.01);②糖尿病组大鼠肾小管上皮细胞α-SMA、Vimentin和TGF-β1阳性表达均显著高于对照组,α-SMA表达和TGF-β1表达呈正相关(rs=0.810,P<0.01)。③氯沙坦组尿蛋白排泄量、肾小管间质损伤和间质纤维化程度较糖尿病组减轻,肾小管上皮细胞α-SMA、Vimentin与TGF-β1表达强度较糖尿病组显著下调(P<0.01)。【结论】①糖尿病大鼠肾脏病理进程中存在TEMT;②氯沙坦可下调糖尿病大鼠肾小管上皮细胞TGF-β1、Vimentin、α-SMA表达,阻抑糖尿病肾小管上皮细胞发生TEMT而发挥肾脏保护作用。     

Voluntary Oral Administration of Losartan in Rats

Gavage is a widely performed technique for daily dosing in laboratory rodents. Although effective, gavage comprises a sequence of potentially stressful procedures for laboratory animals that may introduce bias into experimental results, especially when the drugs to be tested interfere with stress-dependent parameters. We aimed to test vehicles suitable for drug delivery by voluntary ingestion in rats. Specifically, Male Wistar rats (age, 2 to 3 mo) were used to test nut paste (NUT), peanut butter (PB), and sugar paste (SUG) as vehicles for long-term voluntary oral administration of losartan, an angiotensin II receptor blocker. Vehicles were administered for 28 d without drug to assess effects on the glucose level and serum lipid profile. Losartan was mixed with vehicles and either offered to the rats or administered by gavage (14 d) for subsequent quantification of losartan plasma levels by HPLC. After a 2-d acclimation period, all rats voluntarily ate the vehicles, either alone or mixed with losartan. NUT administration reduced blood glucose levels. The SUG group had higher concentrations of losartan than did the gavage group, without changes in lipid and glucose profiles. Our results showed that NUT, PB, and SUG all are viable for daily single-dose voluntary ingestion of losartan and that SUG was the best alternative overall. Drug bioavailability was not reduced after voluntary ingestion, suggesting that this method is highly effective for chronic oral administration of losartan to laboratory rodents.Oral administration, whether by gavage or voluntary ingestion, is a common method for providing a single daily dose of drug to animal models. Gavage is widely performed for precise oral dosing in rodents, particularly in efficacy, toxicity, and drug discovery studies. This technique, applicable in unanesthetized animals, is a rapid and efficient mean of accurately delivering fixed doses of the drug to be tested.³⁰ However, gavage comprises a sequence of procedures that are potentially stressful for laboratory animals. The removal of an animal from its cage, its manual restraint, and the insertion of a flexible or rigid dosing cannula into the esophagus with direction to the stomach all cause high levels of stress, even in trained animals.^2,5 In addition, the use of gavage is associated with welfare issues when it is done by inexperienced people or in long-term studies.¹³ Indeed, gastroesophageal aspiration and pulmonary injury represent recurrent complications of gavage dosing of rodents that can be triggered by technical errors.⁸ Moreover, the use of gavage for various drugs and vehicles can elicit a significant stress response in a vehicle- and dose-volume–dependent fashion.⁵When testing antihypertensive drugs, a noninvasive and stress-free method for drug delivery is crucial, because any source of external stress on rodents can significantly increase heart rate and blood pressure^3-5,18 and therefore potentially confound the experimental results.Several alternatives to gavage, which require less human involvement, have been tested in recent years. The administration of a drug mixed with an attractive vehicle by voluntary ingestion seems to be an effective, noninvasive method.^12,15 In previous attempts to refine the gavage procedure, nut paste has been successfully used for analgesic drug delivery^1,12,15,17 and is a promising option for estrogen administration.¹⁴ Other alternatives involve the use of pill dosing method,³² flavored gelatin (‘jello’) preparations,¹⁰ sugar cookie dough,⁷ honey,¹⁹ and syringe-feeding.²In our study, we used nut paste (NUT), peanut butter (PB), and sugar paste (SUG) as drug vehicles due to their palatability, consistency, and previously reported results. We aimed to investigate the suitability of these vehicles for voluntary oral administration and, as an alternative method to gavage, for the chronic administration of losartan to laboratory rats. We hypothesized that low amounts of these vehicles, even when administered to rats over a long period of time, would not induce relevant changes in blood glucose or lipid profiles and would efficiently deliver the tested drug, as assessed by losartan serum concentrations. Accordingly, we further hypothesized that the serum concentrations of the drug delivered by voluntary ingestion would be at least as high as that obtained by using gavage.     

氯沙坦对糖尿病大鼠肾小管间质P38MAPK表达的影响

【目的】探讨P38丝裂原活化的蛋白激酶（P38MAPK）与糖尿病肾病（DN）肾小管间质病变的关系,及氯沙坦对其的影响。【方法】雄性Wistar大鼠,随机分为正常对照组和模型组,后者经STZ诱导糖尿病模型成功后再随机分为糖尿病模型组和氯沙坦干预组。8周后检测各组大鼠24 h尿蛋白、血肌酐;留取肾组织行HE和MASSON染色,观察肾小管间质损伤指数、肾间质胶原面积;免疫组化检测肾小管间质磷酸化P38MAPK以及TGFβ1表达,并做半定量分析。【结果】①与对照组相比,糖尿病模型组大鼠尿蛋白排泄量、肾小管间质损伤指数和肾间质胶原面积明显增加（P〈0.01）;②糖尿病组大鼠肾小管间质磷酸化P38MAPK、TGFβ1表达均显著高于对照组（P〈0.01）;③氯沙坦组尿蛋白排泄量、肾小管间质损伤程度较糖尿病组减轻,肾小管间质磷酸化P38MAPK、TGFβ1表达较糖尿病组显著下调（P〈0.01）。【结论】糖尿病肾病小管间质病变的病理过程中存在P38MAPK的活化;氯沙坦可阻抑糖尿病大鼠肾小管间质P38MAPK活化,下调TGFβ1表达而发挥肾脏保护作用。     

Abnormalities of in vitro Thyroid Function Tests in Renal Disease

In vitro tests of thyroid function, have been performed in 70euthyroid patients with chronic renal disease. Abnormal valueswere observed in 54 out of 87 blood samples (70 per cent). Thecharacteristic pattern was an elevated triiodothyronine (T₃)resin uptake and a subnormal serum total thyroxine (T₄). Theparameters derived from these tests, the free thyroxine index(FTI), and the free thyroxine factor (FTF) also did not alwaysprovide correct diagnostic information, being abnormal in 21per cent and 14 per cent respectively. The ‘free thyroxine’was normal in all except two patients. Thyroxine-binding globulin(TBG) capacity was normal in 67 out of 80 cases (84 per cent).Patients with renal failure did not demonstrate the normal relationshipbetween T₃ resin uptake and free TBG. It is postulated thatthe abnormalities may be due to two factors; firstly, the presencein the serum of an unknown substance displacing thyroxine fromTBG, and secondly, changes in ionic strength altering the bindingproperties of TBG. The thyroid tests returned to normal afterrenal transplantation.     

Postnatal Changes in Renal Glomerular Blood Flow Distribution in Puppies

The intrarenal distribution of radionuclide microspheres injected into the thoracic aorta was used to examine glomerular blood flow distribution (GBFD) in 26 healthy, unanesthetized puppies, ranging in age from 5 h to 42 days, and in 5 adult dogs. For analysis, the cortex was divided into four equally thick zones designated zone I (subcapsular) to zone IV (juxtamedullary).During the first 36 h of life, the highest flow rate was in zone II, which received 35.5+/-2.0%/g, compared with 26.8+/-1.4% to zone I, 23.7+/-1.4% to zone III, and 13.4+/-1.4% to zone IV. At age 6 wk, zone I had the highest rate of perfusion (48.6+/-2.1%, compared with 28.8+/-1.4% in zone II, 15.8+/-0.8%, in zone III, and 6.8+/-0.6% in zone IV). The 6-wk old animals resembled the adult animals, except for relatively greater perfusion per gram of zone I in the former group. Changes in relative GBFD did not correlate with those in arterial pressure or peripheral hematocrit.The distribution of glomeruli among the four zones of the cortex followed its own pattern of development. At birth and at 6 wk, the greatest density of glomeruli was in zone I (50.6+/-5.4 and 42.7+/-3.9%/g respectively, as compared with 24.1+/-2.9% in adults); in adults zone II contained the greatest density (39.1+/-1.6%).At birth the relative perfusion of glomeruli in zone I was only one-fifth that of glomeruli in zone IV, with intermediate values in zones II and III. By 6 wk of age, increased perfusion of the outer cortical glomeruli resulted in rates of flow in the four zones that did not differ significantly from each other. Relative perfusion in zone I continued to increase, so that in the adult animals perfusion in that zone was significantly greater than in the three deeper zones.These data demonstrate the marked hemodynamic changes that take place within the kidney during the first few weeks of life. The relatively greater blood flow of the most deeply situated nephrons in the early postnatal period suggests ascendancy of this population of nephrons and may have important functional implications.     

Changes in Operant Behavior of Rats Exposed to Lead at the Accepted No-Effect Level

Abstract

Severe lead intoxication has been documented with several serious symptoms of the nervous system such as encephalopathy, mental retardation, hyperactivity, tremors, stereotyped behavior, irritability, and aggressiveness. Severe clinical manifestations of both acute and chronic lead poisoning have become increasingly rare during recent years. However, there are still essential problems such as risk estimation of increased blood-lead levels and determination of the no-effect level. More recently, it has been suggested that lead exposure at levels too low to cause gross symptoms might still induce subclinical functional alterations in the central nervous system. In particular, chronic exposure to small amounts of inorganic lead must still be considered an environmental hazard.     

高血压病患者动态动脉硬化指数与早期肾脏异常的关系

目的 探讨高血压病患者动态动脉硬化指数与早期肾脏损害征象之间的关系.方法 随机检测72例高血压病患者的动态动脉硬化指数(AASI)、动态血压、动态脉压,检测患者的肌酐、尿微量白蛋白,计算肾小球滤过率.按照患者的AASI分为两组:AASI低水平组(AASI≤0.51)40例,AASI高水平组(AASI0.51)32例.比较两组各参数指标的差别;并对各参数指标进行Pearson相关性分析和多因素Logistic回归分析.结果 与AASI低水平组相比,AASI高水平组尿微量白蛋白量增高(P<0.05),肾小球滤过率明显降低(P<0.01).单因素分析显示,AASI与尿微量白蛋白正相关(r=0.32,P<0.001),与肾小球滤过率呈负相关(r=0.44,P<0.001).在校正了混杂因素后,AASI对早期肾脏功能损害的OR为2.18(P=0.008,95%CI:1.76～4.34).结论 AASI增加与高血压早期肾损害相关.     

Renal Abnormalities and Vascular Complications in Primary Hyperaldosteronism. Evidence on Tertiary Hyperaldosteronism

The frequency of underlying renal or renal artery disease, andthe incidence of vascular complications were reviewed in a seriesof 136 cases of primary hyperaldosteronism. This was in orderto investigate the possible existence of ‘tertiary’hyperaldosteronism, and to examine the commonly held view thatprimary hyperaldosteronism is a relatively benign form of hypertension. Ten cases (7·4 per cent) had evidence of renal arterystenosis and eleven (8·1 per cent) parenchymatons renaldisease. In comparison with the reported frequency in largegeneral series of hypertensives, these data show no evidenceof an excess of underlying renal disease. It is unlikely, therefore,that autonomous aldosterone secreting adenomata occur commonlyas a consequence of prolonged secondary hyperaldosteronism. Four cases (2·9 per cent) had evidence of the malignant-phaseof hypertension, and over a mean observation time of 5·9years, 31 cases (22·8 per cent) developed 39 vascularcomplications. It appears, therefore, that vascular complicationsare not rare in primary hyperaldosteronism, and early and effectivetreatment is thus necessary.     

氯沙坦对SHR心肌及心肌血管周围胶原影响的实验研究

【目的】探讨氯沙坦治疗对自发性高血压大鼠 (SHR)左心室心肌及心肌周围胶原纤维增殖的影响。【方法】以 4 2只 12周龄雄性SHR为对象 ,分为氯沙坦治疗组 (SHR L ,30mg·kg-1·d-1)及未服药组(SHR C) ,每组 2 1只 ;另以 2 1只WKY大鼠为正常对照组。治疗组降压治疗 12周。同步测量各组收缩压 ,测量左心室重量 ,计算心脏左室重量与体重比值 (LV/BW ) ,测量心肌间质胶原容积分数 (CVF)和心肌血管周围胶原面积 (PVCA)。【结果】①SHR L组LV/BW明显降低 (P <0 .0 1) ,随治疗时间的延长其降低程度越明显。②WKY组 12～ 2 4周龄CVF、PVCA明显增加 ,差异有显著性 (P <0 .0 5 )。SHR C组随周龄增加其CVF、PVCA值亦升高 (P <0 .0 5 ) ;与同周龄WKY比较 ,CVF及PVCA明显升高 (P <0 .0 5 )。SHR L组与SHR C组比较 ,CVF、PVCA明显下降 (P <0 .0 5 ) ,接近WKY组 (P >0 .0 5 )。【结论】氯沙坦使胶原异常增生明显得到抑制 ,并促进胶原蛋白降解 ,从而预防和阻止心肌纤维化 ,使SHR肥厚左室明显逆转 ,     

甲钴胺预防糖尿病大鼠外周神经结构异常的效果

目的：探讨甲钴胺预防不同病程糖尿病外周神经病变的有效性。方法：80只SD大鼠随机选取16只作为正常对照组（NC组）;64只四氧嘧啶诱导糖尿病模型,模型成功后根据外源胰岛素控制血糖水平,将血糖控制较好的大鼠分为ID-1组和M-ID-1组各16只;血糖控制较差的分为ID-2组和M-ID-2组各16只,M-ID-1和M-ID-2组均每日肌注甲钴胺500μg/kg。12周后各组大鼠麻醉下切除坐骨神经,在光镜和电镜下检测坐骨神经纤维结构,并监测果糖胺等糖代谢情况。结果：与NC组比较,其它各组均出现神经结构异常。与其它模型组比较,M-ID-1组（果糖胺1.0 mmol/L）坐骨神经纤维结构异常明显减少（P〈0.05）;M-ID-2组（果糖胺1.2 mmol/L）与ID-2组比较,纤维结构改变无差别。结论：甲钴胺对外周神经病变的延缓效应在一定病程内受血糖的影响,血糖控制较好则效果较好。     

Influence of Renal Failure on Ciprofloxacin Pharmacokinetics in Rats

Ciprofloxacin pharmacokinetics have been shown to be modified in patients with renal failure (e.g., the intestinal secretion of ciprofloxacin is increased). This study investigated the influence of renal failure on the pharmacokinetics of ciprofloxacin following oral and parenteral administration to rats of a dose of 50 mg/kg of body weight. After parenteral administration, only renal clearance (CL_R) was reduced in nephrectomized rats (5.3 ± 1.4 versus 17.8 ± 4.7 ml/min/kg, P < 0.01, nephrectomized versus control rats). However, nonrenal clearance was increased in nephrectomized rats (32 ± 4 versus 15 ± 5 ml/min/kg, P < 0.01, nephrectomized versus control rats), suggesting compensatory mechanisms for reduced renal function. After oral administration, apparent total clearance and CL_R were reduced (P < 0.01) in nephrectomized rats (117 ± 25 and 6.8 ± 4.4 ml/min/kg, respectively) compared with the values for control rats (185 ± 9 and 22.6 ± 5.3 ml/min/kg, respectively) and the area under the concentration-time curve was higher (P < 0.01) for nephrectomized rats (436.3 ± 90.5 mg · min/liter) than for control rats (271.3 ± 14.3 mg · min/liter). Terminal elimination half lives in the two groups remained constant after oral and parenteral administration. These results suggest an increased bioavailability of ciprofloxacin in nephrectomized rats, which was confirmed by a nonlinear mixed-effect model.     

Renal Adaptation to a Low Phosphate Diet in Rats: BLOCKADE BY ACTINOMYCIN D

The major renal adaptive changes in response to selective dietary phosphate restriction are a marked reduction in urinary excretion of phosphate and an increased urinary excretion of calcium; at the cellular level, there is selective increase in renal cortical brush border membrane phosphate uptake and increase in specific activity of alkaline phosphatase. In the present study we examined whether these functional and biochemical adaptive changes could be blocked by drugs known to inhibit protein synthesis.Administration of actinomycin D or cycloheximide to rats switched from a diet with normal phosphate content (0.7%) to a diet with low (0.07%) phosphate content either completely (actinomycin D) or partially (cycloheximide) prevented the expected decrease in urinary excretion of phosphate and increase in the urinary excretion of calcium. The specific activity of alkaline phosphatase measured in crude membrane fraction (washed 100,000 g pellet) from renal cortical homogenate in animals fed a low phosphate diet and treated with actinomycin D or with cycloheximide was significantly lower than in control animals also on a low phosphate diet receiving placebo; but there were no differences between treated and untreated animals in the activities of two other brush border enzymes, gamma-glutamyltransferase and leucine aminopeptidase. Actinomycin D administered to rats maintained on a normal phosphate diet throughout the course of the experiment caused an increase in the urinary excretion of phosphate on the last (6th) day of the experiment but did not change urinary excretion of calcium. In acute clearance experiments, infusion of actinomycin D to rats adapted to a low phosphate diet did not increase fractional excretion of phosphate.In separate experiments, using the same dietary protocol as above, brush border membrane fraction (vesicles) was prepared from renal cortex of rats sacrificed at the end of the experiment. In this preparation Na(+)-dependent (32)Pi and d-[(3)H]glucose uptake and activities of brush border enzymes membrane were determined. Brush border membrane vesicles prepared from rats fed a low phosphate diet showed significantly higher Na(+)-dependent (32)Pi uptake compared with rats fed a normal phosphate diet. This increase in (32)Pi uptake was completely prevented when rats on a low phosphate diet were simultaneously treated with actinomycin D. These differences were specific for (32)Pi transport as no differences were observed in d-[(3)H]glucose uptake among the three groups. There was a positive correlation (r = 0.82, P < 0.01) between (32)Pi uptake and specific activity of alkaline phosphatase measured in aliquots of the same brush border membranes, whereas no such correlation was observed with two other brush border membrane enzymes gamma-glutamyltransferase and leucine aminopeptidase.These observations show that actinomycin D prevents both the functional and cellular renal adaptive changes induced by a low phosphate diet. Taken together, these observations suggest that renal adaptation to a low phosphate diet could be prevented by inhibition of de novo protein synthesis.     

Renal Net Glucose Release In Vivo and Its Contribution to Blood Glucose in Rats

This study describes the contribution of de novo glucose synthesis by the kidney to blood glucose homeostasis in rats. The net glucose release by the kidney in vivo was measured by an isotope-dilution method, which calculated the extent of dilution of injected [¹⁴C]glucose by glucose newly synthesized in the kidney. The extent of dilution was determined from the difference between the decrease of the actual blood glucose concentration and that of the radioactivity of [¹⁴C]glucose, after injecting [¹⁴C]glucose into functionally hepatectomized rats.     

Neurodiagnostic Abnormalities in Patients with Acute Renal Failure: EVIDENCE FOR NEUROTOXICITY OF PARATHYROID HORMONE

Neurological abnormalities are a major cause of morbidity in patients with renal failure. The pathophysiology of these neurological changes is unclear, and the effects on them of dialysis and return of renal function have not been well studied. Studies were done in 31 patients who had acute renal failure (ARF), all of whom were either treated with dialysis within 5 days or did not survive. Studies on these patients included the electroencephalogram (EEG), motor nerve conduction velocity, and plasma Ca⁺⁺ and parathyroid hormone (PTH) levels. Studies were done at the time ARF was diagnosed, after stabilization on dialysis, during the diuretic phase of ARF, and 3 mo after recovery from ARF. In 16 patients with acute or chronic renal failure who did not survive and in nine patients without renal disease who died, measurements were made in brain of content of Na⁺, K⁺, Cl⁻, Ca⁺⁺, Mg⁺⁺, and water.     

硫普罗宁对梗阻性黄疸大鼠肾功能保护作用的研究

目的 探讨硫普罗宁对实验性梗阻性黄疸大鼠肾功能的保护作用及作用机理。方法 SD大鼠胆总管结扎后分2组，每组20只，术后分别用1ml硫普罗宁或生理盐水腹腔注射。另设假手术组20只：分别于术后10d、20d(每组10只)心脏取血测定血清超氧化物歧化酶(SOD)、丙二醛(MDA)含量，同时测定血清肌酐(Cr)、尿素氮(BUN)和直接胆红素(DB)浓度，并对肾脏行光镜下病理形态学观察。结果 血清MDA浓度在梗阻10d即升高，且随胆道梗阻时间延长进一步升高，SOD在梗阻10d即下降，同时伴有血清Cr、BUN、DB的升高和肾脏病理形态学的进行性改变。硫普罗宁治疗组MDA显低于对照组，SOD显高于对照组，并能改善肾组织病理形态。结论 大鼠梗阻性黄疸氧自由基损害是肾损伤的原因，硫普罗宁通过降低血清MDA水平并提高SOD活性，对梗阻性黄疸大鼠的肾脏起保护作用。     

大鼠双侧肾动脉后支结扎术手术入路的研究

目的:介绍一种大鼠背双侧手术入路行双侧肾动脉后支结扎制作肾性高血压模型的新方法。方法:通过对35只Sprague-Dawley(SD)大鼠行背双侧入路双肾动脉后支结扎术,术后一周用2%盐水替代饮水,喂养观察3个月。结果:全组大鼠中死亡6只,存活29只在3个月时血压上升达177.66±10.06mmHg。结论:大鼠背双侧手术入路行双肾动脉后支结扎术是一种手术操作简便且无须显微镜、安全和易于掌握,值得推广的新方法。     

Renal Tubular Sites of Altered Calcium Transport in Phosphate-depleted Rats

Increased calcium (Ca) excretion is characteristic of chronic phosphate (PO(4)) depletion (PD). To study the changes in tubular transport and the site of the hypocalciuric effect of PO(4) administration, clearance and micropuncture experiments were performed in intact rats pair fed either a control diet (0.5% PO(4)) or a PO(4)-depleted (PD) diet (0.01% PO(4)) plus Al(OH(3)) and in parathyroidectomized (PTX) PD rats, infused either with saline or with neutral sodium PO(4).Intact PD rats, compared with intact rats on a control diet, exhibited a lower plasma ultrafiltrable (UF) PO(4) (5.8+/-0.5 vs. 7.8+/-0.3 mg/dl), higher fractional excretion (FE) of Ca (4.1+/-1.2 vs. 0.6+/-0.1%), and reduced FE PO(4) (0.1+/-0.01 vs. 10.2+/-1.8%). Tubular fluid/plasma inulin was lower in the late proximal tubule of PD rats, associated with increases in fractional delivery (FD) from the proximal tubule of Na and Ca.The%FD of Ca to the early distal tubule of PD rats was increased (20+/-3 vs. 11+/-2%), but this difference was abolished by the late distal tubule (5.1+/-1.2 vs. 3.3+/-0.9%). In PTX-PD rats, PO(4) infusion increased plasma UF PO(4) (13.8+/-0.7 vs. 7.8+/-0.7 mg/dl). FE of Ca was reduced (1.08+/-0.35 vs. 4.59+/-1.57%) without correcting the increased Ca delivery to the late distal tubule.These data indicate that PD impairs Ca reabsorption in tubular segments before but not within the distal convoluted tubule, so that hypercalciuria is ultimately a result of decreased Ca transport either in the terminal nephron or in deeper nephrons where PO(4) infusion stimulates Ca transport independent of parathyroid hormone or changes in the filtered load of Ca.     

Renal resistance to parathyroid hormone during phosphorus deprivation.

Because previous studies have demonstrated that renal inorganic phosphate reabsorption is enhanced in rats after dietary phosphorus deprivation, we studied the effects of parathyroid hormone (PTH) upon inorganic phosphate reabsorption in acutely thyroparathyroidectomized rats stabilized on a low phosphorus diet to determine if the phosphaturic response to PTH is impaired during phosphorous depletion. Acutely thyroparathyroidectomized phosphorus-deprived rats responded only minimally to PTH, whereas similarly prepared animals stabilized on a high phosphorus diet exhibited a large phosphaturic response. Base-line urinary cyclic AMP values and PTH-induced increases in cyclic AMP excretion were similar in both groups. In other experiments, dibutyryl cyclic AMP elicited a greatly diminished phosphaturic response in phosphorus-deprived rats, as compared to their high phosphorus counterparts. These results indicate that the renal phosphaturic responses to PTH and cyclic AMP are impaired during dietary phosphorus deprivation. The impaired phosphaturia would contribute to phosphorus conservation and to the replenishment of inorganic phosphate stores after phosphorus depletion.     

Impact of Baseline Renal Function on the Efficacy and Safety of Aliskiren Added to Losartan in Patients With Type 2 Diabetes and Nephropathy

OBJECTIVE

Proteinuric diabetic patients with reduced glomerular filtration rate (GFR) are at high risk of renal and cardiovascular disease progression and treatment-related adverse events. This post hoc analysis assessed the efficacy and safety of aliskiren added to the maximal recommended dose of losartan according to baseline estimated GFR (eGFR) (stage 1–3 chronic kidney disease [CKD]).

RESEARCH DESIGN AND METHODS

In the Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) study, 599 hypertensive patients with type 2 diabetes and nephropathy received 6 months of aliskiren (150 mg daily titrated to 300 mg daily after 3 months) or placebo added to 100 mg losartan and optimal antihypertensive therapy. Exclusion criteria included eGFR <30 ml/min per 1.73 m² and serum potassium >5.1 mmol/l.

RESULTS

Baseline characteristics were similar between treatment groups in all CKD stages. The antiproteinuric effects of aliskiren were consistent across CKD stages (19, 22, and 18% reduction). In the stage 3 CKD group, baseline serum creatinine levels were equal, but renal dysfunction, prespecified as a postrandomization serum creatinine elevation >176.8 μmol/l (2.0 mg/dl) occurred more frequently in the placebo group (29.2 vs. 13.6%, P = 0.032). Serum potassium elevations >5.5 mmol/l (based on a single measurement) were more frequent with aliskiren (22.5 vs. 13.6%) in stage 3 CKD. Adverse event rates were similar between treatments, irrespective of CKD stage.

CONCLUSIONS

Aliskiren added to losartan reduced albuminuria and renal dysfunction and was well tolerated, except for hyperkalemia (stage 3), independent of baseline CKD stage in patients with type 2 diabetes, hypertension, and nephropathy.Renin inhibition is a new treatment modality that blocks the renin-angiotensin-aldosterone system (RAAS) at the first rate-limiting step of the cascade. Because the direct renin inhibitor aliskiren recently was approved for the treatment of hypertension, it seemed a reasonable assumption that this drug would also possess antiproteinuric qualities. In theory, renin inhibition will decrease plasma renin activity and levels of circulating angiotensin I and angiotensin II, leading to more efficient RAAS blockade. A previous study from our group has suggested a higher degree of RAAS blockade by the use of the combination of aliskiren and the angiotensin II receptor blocker irbesartan (1). Whereas this hypothesis was formerly proven only in small studies (1,2), the Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) study (3) was the first double-blind, randomized controlled trial to demonstrate the antiproteinuric ability of aliskiren (300 mg once daily) as an add-on to standard treatment, including the recommended dose of an angiotensin II receptor blocker (losartan), in patients with type 2 diabetes, hypertension, and nephropathy.There is an evident unmet need for improved renoprotective therapies because this patient group constitutes the majority of patients requiring dialysis in the western world (4). Reduction in proteinuria from RAAS blockade has been shown to be associated with improved renal and cardiovascular prognosis (5,6), and although its use remains controversial, albuminuria is the best available surrogate marker for renal protection. Combination treatment with renin inhibition and angiotensin II receptor blockade is evolving as a new antiproteinuric treatment, but not much is known about the impact of underlying renal function on the safety and efficacy of this treatment. The aim of this post hoc analysis was to investigate the efficacy and safety of add-on treatment with aliskiren in the AVOID study across different stages of estimated glomerular filtration rate (eGFR) at baseline.