Role of aldosterone in oxidative stress and renal injury

Recent clinical studies have indicated the utility of mineralocorticoid receptor (MR) antagonists in cardiovascular and renal injuries. Chronic treatment with aldosterone/salt resulted in severe cardiac and renal injuries in rats. Further studies showed that the aldosterone-induced organ injuries were associated with increases in expression of NADPH oxidase components and reactive oxygen species (ROS) levels. Treatment with a selective MR antagonist, eplerenone, prevented the elevation of ROS levels and ameliorated organ injuries. In vitro studies also showed that MR is highly expressed in cultured vascular smooth muscle cells, glomerular mesangial cells and renal fibroblasts. In these cells, aldosterone-induced cell injuries were associated with increases in NADPH oxidase activity and superoxide generation. Further, the aldosterone-dependent cell injuries were markedly attenuated by treatment with eplerenone. These accumulating data support the notion that the aldosterone/MR is involved in the pathogenesis of cardiovascular and renal injuries through NADPH oxidase-dependent ROS production.     

Endothelin antagonists for diabetic and non-diabetic chronic kidney disease

Numerous pre-clinical studies have implicated endothelin-1 in the pathogenesis of diabetic and non-diabetic chronic kidney disease (CKD). Renal endothelin-1 production is almost universally increased in kidney disease. The pathologic effects of endothelin-1, including vasoconstriction, proteinuria, inflammation, cellular injury and fibrosis, are likely mediated by the endothelin A (ETA) receptor. ETA antagonism alone, and/or combined ETA/B blockade, reduces CKD progression. Based on the strong pre-clinical data, several clinical trials using ETA antagonists were conducted. Small trials involving acute intravenous endothelin receptor blockade suggest that ETA, but not ETB, blockade exerts protective renal and vascular effects in CKD patients. A large phase 3 trial (ASCEND) examined the effects of avosentan, an endothelin receptor antagonist, on renal disease progression in diabetic nephropathy. Proteinuria was reduced after 3–6 months of treatment. However the study was terminated due to increased morbidity and mortality associated with avosentan-induced fluid retention. Several phase 2 trials using avosentan at lower doses than in ASCEND, atrasentan or sitaxsentan (the latter two being highly ETA-selective) showed reductions in proteinuria on top of renin-angiotensin system blockade. Infrequent and clinically insignificant fluid retention was observed at the most effective doses. Additional trials using ETA blockers are ongoing or being planned in patients with diabetic nephropathy or focal segmental glomerulosclerosis. Moving forward, such studies must be conducted with careful patient selection and attention to dosing in order to minimize adverse side effects. Nonetheless, there is cause for optimism that this class of agents will ultimately prove to be effective for the treatment of CKD.     

Is Ramipril the pril for diabetes and kidney disease?

Ramipril is safe and effective in the treatment of hypertension and heart failure, but this is not reviewed here. Ramipril is a lipophilic angiotensin-converting enzyme inhibitor suitable for once-daily administration. In addition to decreasing angiotensin II and increasing bradykinin levels, ramipril increases the levels of vasodilatory renal medullary neutral lipids and inhibits platelet-derived growth factor-induced proliferation of glomerulus cells. Ramipril also decreases transforming growth factor-beta in the kidney. Changes in kidney structure and proteinuria are characteristics of the streptozotocin (STZ) rat model of diabetes, and these are prevented by ramipril. In STZ diabetes, doses of ramipril that have no effect on blood pressure reverse vascular hypertrophy. In animal models of kidney failure (subtotal nephrectomy, stroke-prone spontaneously hypertensive rats), ramipril is renoprotective and some of this renoprotective effect is independent of blood pressure lowering. In humans, clinical doses of ramipril probably do not modify glucose metabolism but do reduce the levels of LDL- and HDL-cholesterol. In clinical trials of renal effects, ramipril has been shown to increase cortical nephron flow in hypertension and to reduce proteinuria in patients with and without diabetes and/or hypertension. Some of the smaller clinical trials showed beneficial effects on kidney function with low doses of ramipril that do not lower blood pressure. A large clinical trial in nondiabetic proteinuria, the Ramipril Efficacy in Nephropathy (REIN) trial, has shown that ramipril 1.25 mg/day, which does not lower blood pressure, arrested the decline in glomerular filtration rate and prolonged the time to end-stage renal failure. In diabetic patients who have had a previous cardiovascular event or having one other cardiovascular risk factor, the MICRO-HOPE clinical trial showed that ramipril lowers the combined risk of myocardial infarction, stroke and cardiovascular death by 25%. In conclusion, ramipril has proven beneficial effects in kidney disease alone or in association with diabetes and in diabetes without kidney disease, and is the pril for diabetes and kidney disease. (c) 2001 Prous Science. All rights reserved.     

Drug Discovery for Overcoming Chronic Kidney Disease (CKD): The Endothelin ETB Receptor / Nitric Oxide System Functions as a Protective Factor in CKD

Accelerated cardiovascular disease (CVD) is a frequent complication of renal disease. Chronic kidney disease (CKD) develops hypertension and dyslipidemia, which in turn can contribute to the progression of renal failure. There is general agreement that endothelin-1 (ET-1), which acts through the two subtypes of receptor ET_A and ET_B, plays important physiological roles in the regulation of normal cardiovascular function and that excessive ET-1 production is linked to CVD and CKD. Although selective ET_A or nonselective ET_A/ET_B receptor antagonisms have been recognized as a potential strategy for treatment of several cardiovascular disease, it remains unclear which of the antagonisms is suitable for the individuals with CKD because upregulation of the nitric oxide (NO) system via ET_B receptor is responsible for renal function such as natriuresis, diuresis, and glomerular hemodynamics. Our findings clearly indicate that the blockade of ET receptors, in particular ET_A-receptor antagonism, not only produces a potential renoprotective effect in CKD but also reduces the risk of CVD. In contrast, pharmacological blockade or genetic deficiency of ET_B receptor seems to aggravate CKD and CVD in several experimental models of rats. Moreover, preliminary evidence in patients with CKD also suggests that both selective ET_A- and nonselective ET_A/ET_B-receptor blockade decreases blood pressure but that selective ET_A blockade has additional desirable effects on renal hemodynamics. Thus, at least in CKD, these findings support the notion that ET_B receptor– mediated actions produce a renoprotective effect and that nonselective ET_A/ET_B-receptors blockade seem to offer no advantage over selective ET_A antagonism, and if anything may potentially reduce the benefits.     

Candesartan: nephroprotective effects and treatment of diabetic nephropathy

Candesartan shows beneficial end-organ effects in the kidney. Some of these appear to be related not to the reduction in systemic blood pressure induced by candesartan, but to its blockage of intrarenal angiotensin II type I (AT1) receptors. Initial studies have shown that renal vascular resistance was reduced in patients with hypertension receiving candesartan, and urinary albumin excretion was reduced in patients with type 2 diabetes mellitus and concomitant microalbuminuria or proteinuria. These findings, together with the results of recently published large randomized studies involving diabetic patients with hypertension treated with other angiotensin II receptor blockers, indicate that this class of drugs is beneficial in preventing the development or progression of diabetic nephropathy. This review summarizes the large body of findings related to these renoprotective effects and reported during experimental and clinical research on candesartan for the treatment of diabetic nephropathy.     

Aldosterone and renal injury

Our recent efforts have been focused on the mechanisms responsible for the progression of aldosterone-induced renal injury. We have demonstrated in rats that chronic treatment with aldosterone (0.75 micro g/H, SC) and 1% NaCl (in drinking solution) results in severe proteinuria and glomerular injury, characterized by cell proliferation and mesangial matrix expansion. Increased renal cortical NAD(P)H oxidase expression, reactive oxygen species (ROS) generation, and mitogen-activated protein kinase (MAPK) activation were also observed. Treatment with a selective mineralocorticoid receptor antagonist, eplerenone(0.125% in chow), or an antioxidant, tempol (3 mM in drinking solution), prevented elevations of ROS levels and MAPK activity, as well as ameliorating glomerular injury, indicating that aldosterone-induced glomerular injury is associated with redox-sensitive MAPK activation. In vitro studies showed that mineralocorticoid receptors are highly expressed in rats mesangial cells, particularly in the cytoplasm. Aldosterone (100 nM) application activates MAPK and causes cellular proliferation and deformation. These data suggest that aldosterone contributes to the progression of glomerular injury through its direct actions.     

The antiproteinuric effect of ACE inhibition in renal disease

Proteinuria due to non-steroid-responsive renal disease may be harmful. Firstly, because it may cause a nephrotic syndrome, and, secondly, because it is, like hypertension, associated with an increased risk of progressive renal damage and loss of renal function over the years. Until recently, only non-steroidal antiinflammatory drugs (NSAIDs) were available to reduce proteinuria in such patients. Due to their potential side-effects, however, NSAIDs have never been widely used as antiproteinuric agents. In 1985 some studies were published showing that inhibition of angiotensin-converting enzyme (ACE) not only reduced the elevated blood pressure in rats with chronic renal failure (experimentally induced by renal ablation or by induced diabetic nephropathy), but also prevented the development of glomerular damage with proteinuria and loss of renal function in these animals. This beneficial effect of ACE inhibition was attributed to the prevention of glomerular hypertension. At the same time it was reported that ACE inhibition could reduce proteinuria in patients with advanced diabetic nephropathy. ACE inhibitors might thus be an attractive alternative for NSAIDs as antiproteinuric treatment, possibly being renoprotective, and being generally well-tolerated.     

Which antihypertensive drugs are the most nephroprotective and why?

Importance of the field: Hypertension is a major independent risk factor for kidney disease and for faster renal function loss. Choice of antihypertensive strategies with highest nephroprotective effect is crucial to prevent or reverse progression to end stage renal disease (ESRD).

Areas covered in this review: The present review focuses on the role of hypertension in the progression of chronic kidney disease (CKD), the renoprotective effects of different antihypertensive therapies, and the blood pressure levels that should be targeted in different patient populations. To this end, the PubMed (1975 – 2010) database was searched for English-language articles, using the following keywords: hypertension, kidney disease, ACE-inhibitor, angiotensin receptor blocker, aldosterone antagonist, renin inhibitor, proteinuria.

What the reader will gain: A comprehensive review of data on the association between hypertension and progression of chronic nephropathies and on the antihypertensive treatments with highest nephroprotective effects.

Take home message: Blood pressure should be targeted to 140/90 mmHg or less in patients with hypertension but no renal injury and 130/80 mmHg or less in those with CKD. Amongst different antihypertensive drugs, renin angiotensin aldosterone system (RAAS) inhibitors have an incremental nephroprotective effect in proteinuric patients. Maximal RAAS inhibition should be aimed to optimize renoprotection in hypertensive patients with CKD and proteinuria.     

Valsartan and the kidney: present and future

Angiotensin (Ang) II type 1 (AT1) receptor antagonists are orally active drugs that specifically block the subtype 1 of Ang receptors. In contrast to AT1 receptor antagonists, angiotensin-converting enzyme (ACE) inhibitors block the actions of Ang II incompletely. Furthermore, the bradykinin-potentiating effects of ACE inhibitors may contribute to the mechanism of action of ACE inhibitors. Data in experimental animals suggest that AT1 receptor antagonists decrease the glomerular filtration rate (GFR) to a lesser degree than ACE inhibitors. The greater effect of ACE inhibitors in decreasing glomerular pressure was attenuated with a bradykinin antagonist. In rat models of renal damage with proteinuria, acute reduction of proteinuria was seen with ACE inhibitors but not with AT1 receptor antagonists, whereas long-term reductions of proteinuria were of similar magnitude with both agents. Renal histology after several months revealed that AT1 receptor antagonists and ACE inhibitors were equally renoprotective in various renal damage models. AT1 receptor antagonists, like ACE inhibitors, exhibit a natriuretic effect equal to moderate doses of a thiazide diuretic. In patients with severe volume depletion, use of AT1 receptor antagonists may lead to acute renal failure. Valsartan was tested in a double-blind trial in patients with moderate to severe renal failure and led to a substantial decrease in diastolic and systolic blood pressure, whereas there was no difference from placebo for changes in GFR. Urine protein increased with placebo and decreased with valsartan. The data indicate that valsartan in renal failure patients is effective in lowering blood pressure while leaving renal excretory function unaltered. Whether there is a renoprotective effect can only be shown in long-term trials, which are under way.     

Molecular mechanisms and therapeutic strategies of chronic renal injury: renoprotective effects of aldosterone blockade

Recent clinical and pre-clinical studies have indicated the utility of mineralocorticoid receptor (MR) antagonists in renal injury. We have demonstrated in rats that chronic treatment with aldosterone results in severe proteinuria and renal injury, characterized by glomerular changes, tubulointerstitial fibrosis, and collagen accumulation. We also observed increased reactive oxygen species (ROS) generation and mitogen-activated protein kinases (MAPKs) activity in renal cortical tissues. Treatment with a selective MR antagonist, eplerenone, prevented elevation of ROS levels and MAPK activity, as well as ameliorating renal injury. In vitro studies revealed that MRs are highly expressed in rat glomerular mesangial cells (RMC) and rat renal fibroblasts. In RMC, aldosterone induces cellular injuries through NADPH oxidase-dependent ROS production and/or MAPK activation. Aldosterone-induced renal cellular injuries were markedly attenuated by treatment with eplerenone. These data suggest that aldosterone induces renal injury through activation of MRs and support the notion that MR blockade has beneficial effects on aldosterone-dependent renal injury through mechanisms that cannot be simply explained by hemodynamic changes. In this review, we summarized our recent findings pertaining to the roles of aldosterone and MRs in the pathogenesis of renal injury. Potential molecular mechanisms responsible for aldosterone/MR-induced renal injury were also discussed.     

Comparison between the antiproteinuric effects of the calcium channel blockers benidipine and cilnidipine in combination with angiotensin receptor blockers in hypertensive patients with chronic kidney disease

Aims: Benidipine, an L-/T-type calcium channel blocker, dilates renal efferent and afferent arterioles and reduces glomerular pressure; therefore, it may exert renoprotective effects. We conducted an open-labeled randomized trial to compare the effects of benidipine with cilnidipine in hypertensive patients with chronic kidney disease (CKD).

Methods: The patients who were already being treated with angiotensin receptor blockers (ARBs) received one of the following treatment regimens: benidipine at a dose of 2 mg/day that was increased up to a dose of 8 mg/day (benidipine group; n = 118) or cilnidipine at a dose of 5 mg/day that was increased up to a dose of 20 mg/day (cilnidipine group; n = 115).

Results: After 12 months of treatment, we observed a significant and comparable reduction in the systolic and diastolic blood pressure in both groups. The urinary protein:creatinine ratio was significantly decreased in both groups after 3 months of treatment and thereafter; however, the difference between both groups was not significant after 12 months of treatment. Benidipine exerted an antiproteinuric effect to a greater extent than cilnidipine in patients with diabetes.

Conclusion: The addition of benidipine as well as cilnidipine reduces urinary protein excretion in hypertensive patients with CKD who are already being administered ARBs.     

Mechanisms and management of proteinuria in kidney transplant patients

Proteinuria is a common complication occurring after kidney transplantation. It is associated with an increased risk of renal failure and patient death. Treatment with ACE inhibitors or angiotensin receptor antagonists (blockers) has been shown to reduce proteinuria after kidney transplantation, as well as improve both graft and patient survival. An increase in proteinuria has been observed in some patients after initiation of sirolimus therapy. Although the mechanism of this remains unclear, high proteinuria at baseline and poor renal function at baseline have been identified as potential risk factors for the development of proteinuria after conversion to sirolimus. Initiation of sirolimus therapy is not recommended in patients with early histological indicators of glomerular damage; however, in patients with healthy grafts, sirolimus may prevent future glomerulosclerosis. Early treatment with an ACE inhibitor and sirolimus, prior to the appearance of glomerular changes, may result in better outcomes.     

Co-administration of ezetimibe enhances proteinuria-lowering effects of pitavastatin in chronic kidney disease patients partly via a cholesterol-independent manner

Since co-administration of ezetimibe, a specific inhibitor of cholesterol absorption into the intestine, has been shown to augment lipid-lowering effects of statins, ezetimibe plus statins is a novel therapeutic strategy for the treatment of dyslipidemia in high-risk patients. Statins have been shown to ameliorate renal function and reduce proteinuria in patients with chronic kidney disease (CKD). However, effects of co-administration of ezetimibe with statins on renal damage and dysfunction in CKD patients remain unknown. In this study, we examined whether co-administration of ezetimibe with pitavastatin could augment renoprotective properties of pitavastatin in non-diabetic CKD patients with dyslipidemia. Total cholesterol, LDL-cholesterol and triglycerides levels were reduced more by co-administration of ezetimibe (10 mg/day) with pitavastatin (2 mg/day) (n = 10) than by pitavastatin alone (n = 10). In addition, ezetimibe plus pitavastatin treatment produced significant incremental reduction in proteinuria related to pitavastatin therapy alone. In univariate analyses, proteinuria was correlated with plasma levels of total cholesterol, LDL-cholesterol, triglycerides, HDL-cholesterol (inversely), asymmetric dimethylarginine, an endogenous nitric oxide synthase inhibitor, and urinary excretion levels of L-fatty acid binding protein (L-FABP), a marker of tubular injury and 8-hydroxydeoxyguanosine (8-OHdG), an oxidative stress marker. Multiple stepwise regression analysis revealed that LDL-cholesterol (p < 0.001) and urinary excretion levels of L-FABP (p = 0.001) and 8-OHdG (p < 0.001) were independently related to proteinuria (R² = 0.969). Our present study demonstrated for the first time that co-administration of ezetimibe enhanced proteinuria-lowering effects of pitavastatin in non-diabetic CKD patients partly via a cholesterol-independent manner. Ezetimibe may have pleiotropic actions that could contribute to renoprotective properties of this lipid-lowering agent.     

Statins can improve proteinuria and glomerular filtration rate loss in chronic kidney disease patients,further reducing cardiovascular risk. Fact or fiction?

Introduction: The prevalence of chronic kidney disease (CKD), a risk factor for cardiovascular disease (CVD), is increasing worldwide. Statin treatment, the cornerstone of prevention or treatment of CVD, might have beneficial effects on urine protein excretion and renal function as determined by the glomerular filtration rate, whereas it might protect from acute kidney injury (AKI), mainly due to contrast-induced AKI. These beneficial effects on CKD may not be drug class effects; specific statins at specific doses may help prevent CKD deterioration and reduce CVD risk. We analysed all statin studies that had renal and CVD endpoints as main outcome measures. MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched up to February 2015.

Areas covered: We consider the effects of statins on microalbuminuria, proteinuria, glomerular filtration rate, AKI associated with angiography or percutaneous coronary intervention and on CVD event rates in patients with CKD.

Expert opinion: Current evidence points towards the need to prescribe high-potency statins in patients with CKD, before a major decline in kidney function occurs. This may reduce CVD risk and delay the progress of CKD. Administration of either atorvastatin or rosuvastatin can prevent contrast-induced AKI before angiography or percutaneous coronary intervention. The combination of simvastatin + ezetimibe may decrease vascular events in patients with advanced CKD.     

Drug Discovery for Overcoming Chronic Kidney Disease (CKD): Development of Drugs on Endothelial Cell Protection for Overcoming CKD

Chronic kidney disease (CKD) is becoming a major public health problem worldwide. It is important to protect endothelial function in CKD treatment because injury of the endothelium is a critical event for the generation and progression of CKD. Recently, clinical studies showed that nifedipine, an antihypertensive drug, acts as a protective agent of endothelial cells (ECs). Nifedipine is reported to partially decompose to a nitrosonifedipine that has high reactivity against lipid-derived radicals in vitro. However, it is still unclear whether nitrosonifedipine is a biologically active agent against endothelial injury. We observed that nitrosonifedipine was converted to radical form by reaction with cultured ECs. The cumene hydroperoxide mediated cytotoxity was reduced by nitrosonifedipine in cultured human glomerular ECs (HGECs). Also nitrosonifedipine suppressed the expression of TNF-α–induced intercellular cell adhesion molecule-1 in HGECs. Chronic administration of N^ω-nitro-L-arginine methyl ester (L-NAME) caused systemic arterial hypertension, endotherial injury, and renal dysfunction. In L-NAME– induced hypertensive rats, nitrosonifedipine treatment improved not only the acetylcholine-induced vasodilation of the aortic rings, but also renal dysfunction such as increasing the levels of serum creatinine and urinary protein excretion. Our preliminary data suggest that nitrosonifedipine is a new and useful drug for the treatment of CKD involving ameliorating effects on EC disorder.     

Nicotine signaling and progression of chronic kidney disease in smokers

The deleterious health effects of cigarette smoking are far reaching, and it remains the most important modifiable risk factor for improving overall morbidity and mortality. In addition to being a risk factor for cancer, cardiovascular disease and lung disease, there is strong evidence, both from human and animal studies, demonstrating a role for cigarette smoking in the progression of chronic kidney disease (CKD). Clinical studies have shown a strong correlation between cigarette smoking and worsening CKD in patients with diabetes, hypertension, polycystic kidney disease, and post kidney transplant. Nicotine, in addition to its role in the addictive properties of cigarette smoking, has other biological effects via activation of non-neuronal nicotinic acetylcholine receptors (nAChRs). Several nAChR subunits are expressed in the normal kidney and blockade of the α7-nAChR subunit ameliorates the effects of nicotine in animal models of CKD. Nicotine increases the severity of renal injury in animal models including acute kidney injury, diabetes, acute nephritis and subtotal nephrectomy. The renal effects of nicotine are also linked to increased generation of reactive oxygen species and activation of pro-fibrotic pathways. In humans, nicotine induces transitory increases in blood pressure accompanied by reductions in glomerular filtration rate and effective renal plasma flow. In summary, clinical and experimental evidence indicate that nicotine is at least in part responsible for the deleterious effects of cigarette smoking in the progression of CKD. The mechanisms involved are the subject of active investigation and may result in novel strategies to ameliorate the effects of cigarette smoking in CKD.     

Slowing the progression of adult chronic kidney disease: therapeutic advances

When kidney disease of any aetiology results in substantial loss of nephrons, a common clinical syndrome, characterised by hypertension, proteinuria and a progressive decline in renal function, ensues. This observation suggests that common mechanisms may contribute to progressive renal injury and that therapeutic interventions that inhibit these common pathways may afford renal protection. Research to date has identified several mechanisms that may contribute to progressive renal injury including glomerular haemodynamic changes, multiple effects of angiotensin II and detrimental effects of excessive filtration of plasma proteins by injured glomeruli. Clinical trials over the past decade have identified several interventions that are effective in slowing the rate of progression of chronic kidney disease (CKD). The use of ACE inhibitors, angiotensin receptor antagonists or a combination of the two should be regarded as fundamental to any therapy for slowing the rate of CKD progression. Hypertension should be treated aggressively to achieve a blood pressure target of < 130/80 mm Hg. Reduction of proteinuria to < 0.5 g/day should be regarded as an independent therapeutic goal. Although inconclusive, there is some evidence to support moderate dietary protein restriction to 0.6 g/kg/day in appropriate patients. Hyperlipidaemia may contribute to CKD progression and should be treated to reduce cardiovascular risk and potentially improve renal protection. Smoking cessation should be encouraged and, where necessary, assisted. Among diabetic patients tight glycaemic control should be achieved (glycosylated haemoglobin < 7%). These interventions are simple and relatively inexpensive. If applied to all patients with CKD they will result in substantial slowing of renal function decline in many patients and thereby reduce the number who progress to end-stage renal disease and require renal replacement therapy.     

血管紧张肽转换酶抑制剂与血管紧张肽II受体拮抗剂的联合应用

血管紧张肽转换酶抑制剂和血管紧张肽II受体拮抗剂是临床上已证实的非常有效的抗高血压药物 ,在近年来的研究中发现它们在降压的同时还具有显著的心、肾保护作用 ,并且已有一定数量的临床试验结果显示 ,将 2类药物联合应用可以获得更强大的靶器官保护作用 ,并不会增加不良反应。我们需要更多的大规模临床试验来进一步确证血管紧张肽转换酶抑制剂和血管紧张肽II受体拮抗剂联合用药在这方面的有效性和安全性 ,使心、肾功能不全及有蛋白尿的病人获得最有益的治疗。     

Calcium-channel blockers for treatment of diabetic nephropathy.

The use of calcium-channel blockers (CCBs) to reduce proteinuria associated with nephropathy in patients with diabetes mellitus is discussed. Metabolically induced damage to the nephrons in diabetic nephropathy decreases the filtration rate and increases the glomerular plasma flow rate and transcapillary hydraulic pressure. Microalbuminuria, which is predictive of nephropathy in patients with insulin-dependent diabetes mellitus, is associated with the development of clinical proteinuria and increased mortality. Micro-albuminuria should be evaluated periodically in diabetic patients, and antihypertensive therapy should be initiated when proteinuria is present or blood pressure control is needed. CCBs lower blood pressure because they prevent the action of angiotensin II by blocking the entry of calcium into renal vascular smooth muscle. Some CCBs, such as diltiazem and nicardipine, decrease glomerular pressure by increasing efferent arteriolar dilation. Others, such as nifedipine, may dilate both the afferent and efferent arterioles, thus causing increased excretion of protein. Studies in patients with diabetic nephropathy have shown that individual CCBs vary in their effects on proteinuria; this variation is attributable to their different sites of action and different effects on intrarenal activity. The choice of a CCB or an angiotensin-converting-enzyme inhibitor should be based on concomitant disease states and adverse-effect profiles. For control of hypertension in patients with diabetic nephropathy, diltiazem should be considered initially. Nicardipine is effective for short-term use but has not been tested in long-term studies; it should be considered a reasonable alternative.     

芜湖市健康体检人群慢性肾脏疾病患病率及相关危险因素调查

目的： 调查芜湖市健康体检人群慢性肾脏病（CKD）患病率以及以及与CKD相关独立危险因素。方法： 40377名芜湖市健康体检居民（男性24164名、女性16213名）入选横断面研究。测量体重、身高和血压,同时检测血常规、尿常规,血脂和肾功能,计算GFR（eGFR）。eGFR＜ 60 ml/min/1.73 m2,和/或蛋白尿、血尿者被定义为CKD。 结果： 芜湖市健康体检人群CKD流行率为6.3%,男性高于女性（7.1% vs 5.0%）。蛋白尿、血尿及eGFR＜ 60 ml/min/1.73 m2 患病率分别为1.7%、2.2%、2.9%,并随着年龄的增长而增长。经年龄、性别校正后,多因素回归分析显示高尿酸血症、糖尿病、贫血、年龄及高血压为CKD相关独立危险因素（优势比（OR）： 2.28, 1.70, 1.65, 1.48, 和 1.29）。结论： 芜湖市城区人口CKD患病率低于国内其他研究报道,芜湖市人群CKD早期防治中要注意上述危险因素。