严格控制血糖可减少糖尿病肾病的发生或延缓其病程进展,目前降血糖药物有双胍类、磺脲类、格列奈类、噻唑烷二酮类、α-糖苷酶抑制药、二肽基肽酶IV(dipeptide base peptidase 4, DPP-4)抑制药、胰高血糖素样肽1(glucagon like peptide 1, GLP-1)类似物及胰岛素。双胍类、噻唑烷二酮类、DPP-4抑制药及GLP-1类似物不仅仅可控制血糖,而且有保护肾脏、减少尿蛋白、延缓糖尿病肾病发展的作用。
Abstract Metformin, a biguanide drug, is widely prescribed to treat high blood glucose in individuals with type 2 diabetes mellitus. Type 2 diabetes mellitus is a troubling chronic disease and diabetic nephropathy is one of the most important complications of diabetes mellitus. Recent studies suggest that metformin, in addition to its efficacy in treating type 2 diabetes, may also have therapeutic efficacy in other conditions, including diabetic nephropathy or ameliorative property against tubular cell injury. Moreover, metformin significantly decreases albuminuria in patients with type 2 diabetes mellitus. However, the exact mechanisms beyond the effect of metformin on blood glucose are still unknown. Recent studies suggest that the therapeutic effect of metformin is mediated by its action on adenosine monophosphate-activated protein kinase in tissues. Various investigations show that metformin decreases intracellular reactive oxygen species. Metformin protects against tubular injury by restoring the biochemical alterations and regulation of oxidative stress on renal tubules. It also protects podocytes in nephropathy of diabetes. These findings can more strongly potentiate the clinical use of metformin in the prevention of nephropathy of diabetes. In this regard, to better understand the metformin nephroprotective properties, more experimental rat models and clinical studies are needed.
KIMJ,SHONE,KIM CS,et al.Renal podocyte injury in a rat model of type 2 diabetes is prevented by metformin[J].,DOI:10.1155/2012/210821.
Abstract Hyperglycemia promotes oxidative stress and hence generation of reactive oxygen species (ROS), which is known to play a crucial role in the pathogenesis of diabetic nephropathy. Metformin, an oral hypoglycemic drug, possesses antioxidant effects. The aim of this paper is to investigate the protective effects of metformin on the injury of renal podocytes in spontaneously diabetic Torii (SDT) rats, a new model for nonobese type 2 diabetes. Metformin (350鈥塵g/kg/day) was given to SDT rats for 17 weeks. Blood glucose, glycated haemoglobin (HbA1c), and albuminuria were examined. Kidney histopathology, renal 8-hydroxydeoxyguanosine (8-OHdG) levels and apoptosis were examined. In 43-week-old SDT rats, severe hyperglycemia was developed, and albuminuria was markedly increased. Diabetes induced significant alterations in renal glomerular structure. In addition, urinary and renal 8-OHdG levels were highly increased, and podocyte loss was shown through application of the TUNEL and synaptopodin staining. However, treatment of SDT rats with metformin restored all these renal changes. Our data suggested that diabetes-induced podocyte loss in diabetic nephropathy could be suppressed by the antidiabetes drug, metformin, through the repression of oxidative injury.
TANAKAT,HIGASHIJIMAY,WADAT,et al.The potential for renoprotection with incretin-based drugs[J].,2014,86(4):701-711.
Abstract Incretin-based drugs, i.e., glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, are widely used for the treatment of type 2 diabetes. In addition to the primary role of incretins in stimulating insulin secretion from pancreatic 尾-cells, they have extra pancreatic functions beyond glycemic control. Indeed, recent studies highlight the potential beneficial effects of incretin-based therapy in diabetic kidney disease (DKD). Experimental studies using various diabetic models suggest that incretins protect the vascular endothelium from injury by binding to GLP-1 receptors, thereby ameliorating oxidative stress and the local inflammatory response, which reduces albuminuria and inhibits glomerular sclerosis. In addition, there is some evidence that GLP-1 receptor agonists and DPP-4 inhibitors mediate sodium excretion and diuresis to lower blood pressure. The pleiotropic actions of DPP-4 inhibitors are ascribed primarily to their effects on GLP-1 signaling, but other substrates of DPP-4, such as brain natriuretic peptide and stromal-derived factor-1伪, may have roles. In this review, we summarize recent studies of the roles of incretin-based therapy in ameliorating DKD and its complications.
CRAJOINAS RO,ORICCHIO FT,PESSOA TD,et al.Mechanisms mediating the diuretic and natriuretic actions of the incretin hormone glucagon-like peptide-1[J].,2011,301(2):355-363.
Abstract Glucagon-like peptide-1 (GLP-1) is a gut incretin hormone considered a promising therapeutic agent for type 2 diabetes because it stimulates beta cell proliferation and insulin secretion in a glucose-dependent manner. Cumulative evidence supports a role for GLP-1 in modulating renal function; however, the mechanisms by which GLP-1 induces diuresis and natriuresis have not been completely established. This study aimed to define the cellular and molecular mechanisms mediating the renal effects of GLP-1. GLP-1 (1 g路kg(-1)路min(-1)) was intravenously administered in rats for the period of 60 min. GLP-1-infused rats displayed increased urine flow, fractional excretion of sodium, potassium, and bicarbonate compared with those rats that received vehicle (1% BSA/saline). GLP-1-induced diuresis and natriuresis were also accompanied by increases in renal plasma flow and glomerular filtration rate. Real-time RT-PCR in microdissected rat nephron segments revealed that GLP-1 receptor-mRNA expression was restricted to glomerulus and proximal convoluted tubule. In rat renal proximal tubule, GLP-1 significantly reduced Na(+)/H(+) exchanger isoform 3 (NHE3)-mediated bicarbonate reabsorption via a protein kinase A (PKA)-dependent mechanism. Reduced proximal tubular bicarbonate flux rate was associated with a significant increase of NHE3 phosphorylation at the PKA consensus sites in microvillus membrane vesicles. Taken together, these data suggest that GLP-1 has diuretic and natriuretic effects that are mediated by changes in renal hemodynamics and by downregulation of NHE3 activity in the renal proximal tubule. Moreover, our findings support the view that GLP-1-based agents may have a potential therapeutic use not only as antidiabetic drugs but also in hypertension and other disorders of sodium retention.
FUJITAH,MORIIT,FUJISHIMAH,et al.The protective roles of GLP-1R signaling in diabetic nephropathy:possible mechanism and therapeutic potential[J].,2014,85(3):579-589.
Glucagon-like peptide-1 (GLP-1) is a gut incretin hormone that has an antioxidative protective effect on various tissues. Here, we determined whether GLP-1 has a role in the pathogenesis of diabetic nephropathy using nephropathy-resistant C57BL/6-Akita and nephropathy-prone KK/Ta-Akita mice. By in situ hybridization, we found the GLP-1 receptor (GLP-1R) expressed in glomerular capillary and vascular walls, but not in tubuli, in the mouse kidney. Next, we generated C57BL/6-Akita Glp1r knockout mice. These mice exhibited higher urinary albumin levels and more advanced mesangial expansion than wild-type C57BL/6-Akita mice, despite comparable levels of hyperglycemia. Increased glomerular superoxide, upregulated renal NAD(P)H oxidase, and reduced renal cAMP and protein kinase A (PKA) activity were noted in the Glp1r knockout C57BL/6-Akita mice. Treatment with the GLP-1R agonist liraglutide suppressed the progression of nephropathy in KK/Ta-Akita mice, as demonstrated by reduced albuminuria and mesangial expansion, decreased levels of glomerular superoxide and renal NAD(P)H oxidase, and elevated renal cAMP and PKA activity. These effects were abolished by an adenylate cyclase inhibitor SQ22536 and a selective PKA inhibitor H-89. Thus, GLP-1 has a crucial role in protection against increased renal oxidative stress under chronic hyperglycemia, by inhibition of NAD(P)H oxidase, a major source of superoxide, and by cAMP-PKA pathway activation.
LIU WJ,XIE SH,LIU YN,et al.Dipeptidyl peptidase IV inhibitor attenuates kidney injury in streptozotocin-induced diabetic rats[J].,2012,340(2):248-255.
Dipeptidyl peptidase (DPP) IV inhibitors are probably beneficial for preventing diabetic complication and modulating glucagon-like peptide-1 receptor (GLP-1R) expression. The aim of this study was to determine whether the DPP IV inhibitor LAF237 (vildagliptin) has renoprotective qualities in streptozotocin-induced diabetic rats. Diabetic and nondiabetic rats were treated with an oral dose of 4 or 8 mg/kg/day LAF237 or placebo for 24 weeks, and renal injury was observed by light and electron microscopy. We also assessed DPP IV activity, active GLP-1 level, cAMP and 8-hydroxy-deoxyguanosine excretion, and GLP-1R, cleaved caspase 3, and transforming growth factor-尾1 (TGF-尾1) expression. LAF237 significantly decreased proteinuria, albuminuria, and urinary albumin/creatinine ratio, improved creatinine clearance, and dose-dependently inhibited interstitial expansion, glomerulosclerosis, and the thickening of the glomerular basement membrane in diabetic rats. It is noteworthy that LAF237 markedly down-regulated DPP IV activity and increased active GLP-1 levels, which probably prevented oxidative DNA damage and renal cell apoptosis by activating the GLP-1R and modulating cAMP. Renoprotection was also associated with a reduction in TGF-尾1 overexpression. Our study suggests that DPP IV inhibitors may ameliorate diabetic nephropathy as well as reduce the overproduction of TGF-尾1. The observed renoprotection is probably attributable to inhibition of DPP IV activity, mimicking of incretin action, and activation of the GLP-1R.
ISHIBASHIY,NISHINOY,MATSUIT,et al.Glucagon-like peptide-1 suppresses advanced glycation end product-induced monocyte chemoattractant protein-1 expression in mesangial cells by reducing advanced glycationend product receptor level[J].,2011,60(9):1271-1277.
Advanced glycation end products (AGE) and receptor for AGE (RAGE) interaction elicits reactive oxygen species (ROS) generation and inflammatory reactions, thereby being involved in the development and progression of diabetic nephropathy. Recently, we, along with others, found that glucagon-like peptide-1 (GLP-1), one of the incretins and a gut hormone secreted from L cells in the intestine in response to food intake, could have anti-inflammatory and antithrombogenic properties in cultured endothelial cells. However, the effects of GLP-1 on renal mesangial cells are largely unknown. Therefore, to elucidate the role of GLP-1 in diabetic nephropathy, this study investigated whether and how GLP-1 blocked AGE-induced monocyte chemoattractant protein-1 expression in human cultured mesangial cells. Gene and protein expression was analyzed by quantitative real-time reverse transcription polymerase chain reactions, Western blots, and enzyme-linked immunosorbent assay. The ROS generation was measured with dihydroethidium staining. Glucagon-like peptide-1 receptor (GLP-1R) was expressed in mesangial cells. Glucagon-like peptide-1 inhibited RAGE gene expression in mesangial cells, which was blocked by small interfering RNAs raised against GLP-1R. Furthermore, GLP-1 decreased ROS generation and subsequently reduced monocyte chemoattractant protein-1 gene and protein expression in AGE-exposed mesangial cells. An analogue of cyclic adenosine monophosphate mimicked the effects of GLP-1 on mesangial cells. Our present study suggests that GLP-1 may directly act on mesangial cells via GLP-1R and that it could work as an anti-inflammatory agent against AGE by reducing RAGE expression via activation of cyclic adenosine monophosphate pathway. (C) 2011 Elsevier Inc. All rights reserved.
LIW,CUIM,WEIY,et al.Inhibition of the expression of TGF-beta1 and CTGF in human mesangial cells by exendin-4,a glucagon-like peptide-1 receptor agonist[J].,2012,30(3):749-757.
Despite the presence of glucagon-like peptide-1 receptor (GLP-1R) in kidney tissues, its direct effect on diabetic nephropathy remains unclear. The transforming growth factor-β(1) (TGF-β(1)) and the connective tissue growth factor (CTGF) both induce extracellular matrix accumulation and persistent fibrosis in the glomerular mesangium of patients with diabetic nephropathy.Herein, we demonstrate that a GLP-1R agonist, exendin-4, exerts renoprotective effects through its influence on TGF-β(1) and CTGF in human mesangial cells (HMCs), cultured in a high glucose medium.HMCs, cultured in a high glucose medium, were used for the current study. The direct effect of exendin-4 on TGF-β(1) and CTGF expression was confirmed in HMCs. MDL-12330A (a specific adenylate cyclase inhibitor) and PKI14-22 (a protein kinase A inhibitor) were used to examine the role of the cAMP signaling pathway in exendin's anti-fibrosis action.The findings showed that exendin-4 inhibited the proliferation of HMCs, and upregulated the expression of TGF-β(1) and CTGF, induced by high glucose. The effect of exendin-4 is largely dependent on the activation of adenylate cyclase.This study provides new evidence that GLP-1 acts as an antifibrotic agent in HMCs.
ISHIBASHIY,MATSUIT,OJIMAA,et al.Glucagon-like peptide-1 inhibits angiotensin II-induced mesangial cell damage via protein kinase A[J]., 2012,84(3):395-398.
There is a growing body of evidence that renin-system plays a role in . Recently, we have found that (), one of the incretins, a gut hormone secreted from L cells in the intestine in response to food intake, inhibits advanced glycation end product-induced gene expression in mesangial cells thorugh the interaction with the receptor of . However, effects of on -exposed mesangial cells are unknown. This study investigated whether and how blocked the -induced mesangial cell damage in vitro. completely blocked the -induced generation, NF-魏B activation, up-regulation of levels of intercellular molecule-1 and inhibitor-1 in mesangial cells, all of which were prevented by the treatments with H-89, an inhibitor of . The present results demonstrated for the first time that blocked the -induced mesangial cell injury by inhibiting -mediated NF-魏B activation via pathway. Our present study suggests that strategies to enhance the biological actions of may be a promising strategy for the treatment of .
ALTER ML,OTT IM,VON WEBSKYK,et al.DPP-4 inhibition on top ofangiotensin receptor blockade offers a new therapeutic approach for diabetic nephropathy[J].,2012,36(1):119-130.
The need for an improved treatment for diabetic nephropathy is greatest in patients who do not adequately respond to angiotensin II receptor blockers (ARBs). This study investigated the effect of the novel dipeptidyl peptidase-4 inhibitor linagliptin alone and in combination with the ARB telmisartan on the progression of diabetic nephropathy in diabetic endothelial nitric oxide synthase (eNOS) knockout mice.Sixty male eNOS knockout C57BL/6J mice were divided into four groups after receiving intraperitoneal highdose streptozotocin: telmisartan (1 mg/kg), linagliptin (3 mg/kg), linagliptin + telmisartan (3 mg/kg + 1 mg/kg) and vehicle. Fourteen mice were used as non-diabetic controls.After 12 weeks, urine and blood were obtained and blood pressure measured. Glucose concentrations were increased and similar in all diabetic groups. Telmisartan alone reduced systolic blood pressure by 5.9 mmHg versus diabetic controls (111.2 ± 2.3 mmHg vs 117.1 ± 2.2 mmHg; mean ± SEM; P=0.071). Combined treatment significantly reduced albuminuria compared with diabetic controls (71.7 ± 15.3 08g/24 h vs. 170.8 ± 34.2 08g/24 h; P=0.017), whereas the effects of single treatment with either telmisartan (97.8 ± 26.4 08g/24 h) or linagliptin (120.8 ± 37.7 08g/24 h) were not statistically significant. DPP-4 inhibition, alone and in combination, led to significantly lower plasma osteopontin levels compared with telmisartan alone. Histological analysis revealed reduced glomerulosclerosis after Linagliptin alone and in combination with telmisartan in comparison to non treated diabetic animals (p<0.01 and p<0.05). Kidney malonaldehyde immune-reactivity, a marker of oxidative stress, was significantly lower in animals treated with linagliptin.DPP-4 inhibition on top of ARB treatment significantly reduced urinary albumin excretion and oxidative stress in diabetic eNOS knockout mice. Linagliptin on top of an angiotensin II receptor blocker may offer a new therapeutic approach for patients with diabetic nephropathy.
GROOP PH,COOPER ME,PERKOVICV,et al.Linagliptin lowers albuminuriaon top of recommended standard treatment in patients with type 2 diabetes and renal dysfunction[J].,2013,36(11):3460-3468.
OBJECTIVE-Preclinical data suggest that linagliptin, a dipeptidyl peptidase-4 inhibitor, may lower urinary albumin excretion. The ability of linagliptin to lower albuminuria on top of reninangiotensin- aldosterone system(RAAS) inhibition in humans was analyzed by pooling data from four similarly designed, 24-week, randomized, double-blind, placebo-controlled, phase III trials. RESEARCH DESIGN AND METHODS-A pooled analysis of four completed studies identified 217 subjects with type 2 diabetes and prevalent albuminuria (defined as a urinary albumin-to-creatinine ratio [UACR] of 3023,000mg/g creatinine) while receiving stable doses of RAAS inhibitors. Participants were randomized to either linagliptin 5 mg/day (n = 162) or placebo (n = 55). The primary end point was the percentage change in geometric mean UACR from baseline to week 24. RESULTS-UACR at week 24 was reduced by 32% (95% CI 242 to 221; P <0.05) with linagliptin compared with 6% (95% CI -27 to +23) with placebo, with a between-group difference of 28% (95% CI 247 to 22; P = 0.0357). The between-group difference in the change in HbA1c from baseline to week 24 was 20.61% (26.7 mmol/mol) in favor of linagliptin (95% CI -0.88 to 20.34% [29.6 to 23.7 mmol/mol]; P<0.0001). The albuminuria-lowering effect of linagliptin, however, was not influenced by race or HbA1c and systolic blood pressure (SBP) values at baseline or after treatment. CONCLUSIONS-Linagliptin administered in addition to stable RAAS inhibitors led to a significant reduction in albuminuria in patients with type 2 diabetes and renal dysfunction. This observation was independent of changes in glucose level or SBP. Further research to prospectively investigate the renal effects of linagliptin is underway.
BROEKHUIZEN LN,LEMKES BA,MOOIJ HL,et al.Effect of sulodexide on endothelial glycocalyx and vascular permeability in patients with type 2 diabetes mellitus[J].,2010,53(12):2646-2655.
Endothelial glycocalyx perturbation contributes to increased vascular permeability. In the present study we set out to evaluate whether: (1) glycocalyx is perturbed in individuals with type 2 diabetes
SZYMCZAKM,KUZNIARJ,KLINGERM,et al.The role of heparanase in diseases of the glomeruli[J].,2010,58(1):45-56.
ABSTRACT The glomerular basement membrane (GBM) is a kind of net that remains in a state of dynamic equilibrium. Heparan sulfate proteoglycans (HSPGs) are among its most important components. There are much data indicating the significance of these proteoglycans in protecting proteins such as albumins from penetrating to the urine, although some new data indicate that loss of proteoglycans does not always lead to proteinuria. Heparanase is an enzyme which cleaves beta 1,4 D: -glucuronic bonds in sugar groups of HSPGs. Thus it is supposed that heparanase may have an important role in the pathogenesis of proteinuria. Increased heparanase expression and activity in the course of many glomerular diseases was observed. The most widely documented is the significance of heparanase in the pathogenesis of diabetic nephropathy. Moreover, heparanase acts as a signaling molecule and may influence the concentrations of active growth factors in the GBM. It is being investigated whether heparanase inhibition may cause decreased proteinuria. The heparanase inhibitor PI-88 (phosphomannopentaose sulfate) was effective as an antiproteinuric drug in an experimental model of membranous nephropathy. Nevertheless, this drug is burdened by some toxicity, so further investigations should be considered.
SATISHP,ZHU YQ,RAVASIT,et al.Pirfenidone is renoprotective in diabetic kidney disease[J].,2009,20(8):1765-1775.
Although several interventions slow the progression of diabetic nephropathy, current therapies do not halt progression completely. Recent preclinical studies suggested that pirfenidone (PFD) prevents fibrosis in various diseases, but the mechanisms underlying its antifibrotic action are incompletely understood. Here, we evaluated the role of PFD in regulation of the extracellular matrix. In mouse mesangial cells, PFD decreased TGF-beta promoter activity, reduced TGF-beta protein secretion, and inhibited TGF-beta-induced Smad2-phosphorylation, 3TP-lux promoter activity, and generation of reactive oxygen species. To explore the therapeutic potential of PFD, we administered PFD to 17-wk-old db/db mice for 4 wk. PFD treatment significantly reduced mesangial matrix expansion and expression of renal matrix genes but did not affect albuminuria. Using liquid chromatography with subsequent electrospray ionization tandem mass spectrometry, we identified 21 proteins unique to PFD-treated diabetic kidneys. Analysis of gene ontology and protein-protein interactions of these proteins suggested that PFD may regulate RNA processing. Immunoblotting demonstrated that PFD promotes dosage-dependent dephosphorylation of eukaryotic initiation factor, potentially inhibiting translation of mRNA. In conclusion, PFD is renoprotective in diabetic kidney disease and may exert its antifibrotic effects, in part, via inhibiting RNA processing.
RAKUSAND,KUJALP,KRAMER HJ,et al.Persistent antihypertensive effect of aliskiren is accompanied by reduced proteinuria and normalization of glomerular area in Ren-2 transgenic rats[J].,2010,299(4):758-766.
The effects of the inhibitor on blood pressure (BP), end-organ damage, proteinuria, and tissue and plasma () II levels in young and adult heterozygous transgenic () were evaluated and compared with the effect of the type 1 (AT(1)) receptor blocker during treatment and after 12 days after the withdrawal of drug treatments. BP was monitored by telemetry from the age of 32 days on (young ) and at 100 days (adult ). (10 mg路kg(-1)路day(-1) in osmotic minipumps) or (5 mg路kg(-1)路day(-1) in drinking ) treatment was applied for 28 days in young and for 70 days in adult . In young untreated , severe rapidly evolved. Adult untreated exhibited stable established . Both and fully prevented the development of and in young and normalized BP and in adult . After cessation of treatment in both young and adult BP and were persistently reduced, while after withdrawal BP and rapidly increased. In adult -treated proteinuria was significantly reduced compared with (the effect persisting after withdrawal of treatment), and this decrease strongly correlated with normalization of glomerular size in these . In conclusion, and had similar antihypertensive effects during chronic treatment, but the antihypertensive and organoprotective effects of were persistent even after the 12-day washout period. The durable effect on proteinuria can possibly be attributed to the normalization of glomerular morphology.
PARVING HH,BRENNER BM,MCMURRAY JJ,et al.ALTITUDE Investigators.Cardiorenal end points in a trial of aliskiren for type 2 diabetes[J].,2012,367(23):2204-2213.
LI YC.Vitamin D:roles in renal and cardiovascular protection[J].,2012,21(1):72-79.
Great progress has been made in recent years in understanding the expanding roles of the vitamin D endocrine system beyond calcemic regulation, including pathophysiological actions in the kidney and the cardiovascular system. The purpose of this review is to update the recent advance regarding the effects of vitamin D and its analogs on the renal and cardiovascular system.Vitamin D deficiency is not only widely associated with chronic kidney disease and cardiovascular disease in humans, but may also accelerate the disease progression. Dysregulation of vitamin D metabolism caused by renal insufficiency contributes to the low vitamin D status. Preclinical and clinical studies have demonstrated impressive therapeutic outcome with low-calcemic vitamin D analogs in renal and cardiovascular disease. The mechanism underlying the renal and cardiovascular protection involves regulation of multiple signaling pathways by vitamin D including nuclear factor 魏B, Wnt/尾-catenin and the renin-angiotensin system.The renal and cardiovascular protective activity of vitamin D revealed in recent studies has profound clinical implications. Nutritional correction of vitamin D deficiency and treatment with vitamin D analogs could be therapeutic options for renal and cardiovascular problems. New vitamin D analogs with better renal and cardiovascular therapeutic efficacy are highly desired. More randomized trials are needed to address these issues.
DE ZEEUWD,AGARWALR,AMDAHLM,et al.Selective vitamin D receptoractivation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes(VITAL study):a randomised controlled trial[J].,2010,376(9752):1543-1551.
Background Despite treatment with renin angiotensin aldosterone system (RAAS) inhibitors, patients with diabetes have increased risk of progressive renal failure that correlates with albuminuria. We aimed to assess whether paricalcitol could be used to reduce albuminuria in patients with diabetic nephropathy. Methods In this multinational, placebo-controlled, double-blind trial, we enrolled patients with type 2 diabetes and albuminuria who were receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Patients were assigned (1:1:1) by computer-generated randomisation sequence to receive 24 weeks' treatment with placebo, 1 mu g/day paricalcitol, or 2 mu g/day paricalcitol. The primary endpoint was the percentage change in geometric mean urinary albumin-to-creatinine ratio (UACR) from baseline to last measurement during treatment for the combined paricalcitol groups versus the placebo group. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00421733. Findings Between February, 2007, and October, 2008, 281 patients were enrolled and assigned to receive placebo (n=93), 1 mu g paricalcitol (n=93), or 2 mu g paricalcitol (n=95); 88 patients on placebo, 92 on 1 mu g paricalcitol, and 92 on 2 mu g paricalcitol received at least one dose of study drug, and had UACR data at baseline and at least one timepoint during treatment, and so were included in the primary analysis. Change in UACR was: -3% (from 61 to 60 mg/mmol; 95% Cl -16 to 13) in the placebo group; -16% (from 62 to 51 mg/mmol; -24 to -9) in the combined paricalcitol groups, with a between-group difference versus placebo of -15% (95% CI -28 to 1; p=0.071); -14% (from 63 to 54 mg/mmol; -24 to -1) in the 1 mu g paricalcitol group, with a between-group difference versus placebo of -11% (95% CI -27 to 8; p=0.23); and -20% (from 61 to 49 mg/mmol; -30 to -8) in the 2 mu g paricalcitol group, with a between-group difference versus placebo of -18% (95% CI -32 to 0; p=0.053). Patients on 2 mu g paricalcitol showed an early, sustained reduction in UACR, ranging from -18% to -28% (p=0.014 vs placebo). Incidence of hypercalcaemia, adverse events, and serious adverse events was similar between groups receiving paricalcitol versus placebo. Interpretation Addition of 2 mu g/day paricalcitol to RAAS inhibition safely lowers residual albuminuria in patients with diabetic nephropathy, and could be a novel approach to lower residual renal risk in diabetes.
KIM MJ,FRANKEL AH,DONALDSONM,et al.Oral cholecalciferol decreases albuminuria and urinary TGF-β1 in patients with type 2 diabetic nephropathy on established renin-angiotensin-aldosterone system inhibition[J].,2011,80(8):851-860.
Kidney International aims to inform the renal researcher and practicing nephrologists on all aspects of renal research. Clinical and basic renal research, commentaries, The Renal Consult, Nephrology sans Frontieres, minireviews, reviews, Nephrology Images, Journal Club. Published weekly online and twice a month in print.
ZEEUWD,COLLB,ANDRESS D,et a1.The endothelin antagonist atrasentan lowers residual albuminuria in patients with type 2 diabetic nephropathy[J].,2014,25(5):1083-1093.
Abstract Despite optimal treatment, including renin-angiotensin system (RAS) inhibitors, patients with type 2 diabetic nephropathy have high cardiorenal morbidity and mortality related to residual albuminuria. We evaluated whether or not atrasentan, a selective endothelin A receptor antagonist, further reduces albuminuria when administered concomitantly with maximum tolerated labeled doses of RAS inhibitors. We enrolled 211 patients with type 2 diabetes, urine albumin/creatinine ratios of 300-3500 mg/g, and eGFRs of 30-75 ml/min per 1.73 m(2) in two identically designed, parallel, multinational, double-blind studies. Participants were randomized to placebo (n=50) or to 0.75 mg/d (n=78) or 1.25 mg/d (n=83) atrasentan for 12 weeks. Compared with placebo, 0.75 mg and 1.25 mg atrasentan reduced urine albumin/creatinine ratios by an average of 35% and 38% (95% confidence intervals of 24 to 45 and 28 to 47, respectively) and reduced albuminuria鈮30% in 51% and 55% of participants, respectively. eGFR and office BP measurements did not change, whereas 24-hour systolic and diastolic BP, LDL cholesterol, and triglyceride levels decreased significantly in both treatment groups. Use of atrasentan was associated with a significant increase in weight and a reduction in hemoglobin, but rates of peripheral edema, heart failure, or other side effects did not differ between groups. However, more patients treated with 1.25 mg/d atrasentan discontinued due to adverse events. After stopping atrasentan for 30 days, measured parameters returned to pretreatment levels. In conclusion, atrasentan reduced albuminuria and improved BP and lipid spectrum with manageable fluid overload-related adverse events in patients with type 2 diabetic nephropathy receiving RAS inhibitors. Copyright 漏 2014 by the American Society of Nephrology.
WILLIAMS ME,BOLTON WK,KHALIFAH RG,et al.Effects of pyridoxamine incombined phase 2 studies of patients with type 1 and type 2 diabetes and overt nephrop-athy[J].,2007,27(6):605-614.
BACKGROUND/AIMS: Treatments of (DN) delay the onset of . We report the results of safety/tolerability studies in patients with overt and type 1/treated with , a broad inhibitor of advanced glycation.: The two 24-week studies were multicenter Phase 2 trials in patients under standard-of-care. In PYR-206, patients were randomized 1:1 and had baseline serum (bSCr) <or=2.0 mg/dl. In PYR-205/207, randomization was 2:1 and bSCr was <or=2.0 for PYR-205 and >or=2.0 but <or=3.5 mg/dl for PYR-207. Treated patients (122 active, 90 placebo) received 50 mg twice daily in PYR-206; PYR-205/207 patients were escalated to 250 mg twice daily.: Adverse events were balanced between the groups (p = NS). Slight imbalances, mainly in the PYR-205/207 groups, were noted in (from diverse causes, p = NS) and serious adverse events (p = 0.05) that were attributed to pre-existing conditions. In a merged data set, significantly reduced the change from baseline in serum (p < 0.03). In patients similar to the RENAAL/IDNT studies (bSCr >or=1.3 mg/dl, ), a treatment effect was observed on the rise in serum (p = 0.007). No differences in urinary albumin were seen. Urinary also tended to decrease with (p = 0.049) as did the CML and .: These data provide a foundation for further evaluation of this inhibitor in DN.
NAVARRO-GONZáLEZ JF,MUROSM,MORA-FERNáNDEZC,et al.Pentoxifylline for renoprotection in diabetic nephropathy:the PREDIAN study.Rationale and basal results[J].,2011,25(5):314-319.
STATEMENTS OF THE PROBLEM: (DN) is the main cause of (ESRD). -system () blockade is the standard of care; however, a significant proportion of patients progress to ESRD. (PTF) possesses properties suggesting potential renoprotective efficacy. The aim of the for Renoprotection in (PREDIAN) study is to test the efficacy of PTF addition to blockade on the progression of DN. Here we report the study design and the baseline patient characteristics.: This is an investigator-initiated, single-center, prospective, randomized, controlled, clinical trial without any commercial interest, funded by the Spanish Ministry of Science and Innovation. One hundred and sixty-nine type 2 diabetic patients with Stage 3 and 4 chronic (CKD) were randomized to a control group (n=87) or an active group (n=82), which will receive PTF (1200 mg/day) for 24 months. The primary outcome measure is the difference in estimated rate (eGFR) between the groups at the end of the study.: The baseline characteristics of the subjects are as follows: 116 patients (68.6%) with Stage 3 CKD and 53 (31.3%) Stage 4 CKD, age 69±9 years, duration of 15±3 years, eGFR 37±12 ml/min per 1.73 m(2), albuminuria 1.39±1.16 g/day, blood pressure 142±8/86±8 mmHg. Inflammatory cytokines (-α, , and ) and polymorphisms of the coding genes for these molecules are studied.: The PREDIAN study will provide evidence on the renoprotective benefit of PTF in addition to interventions of proven efficacy (blockade) in DN.
Selective vitamin D receptoractivation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes(VITAL study):a randomised controlled trial
Oral cholecalciferol decreases albuminuria and urinary TGF-β in patients with type 2 diabetic nephropathy on established renin-angiotensin-aldosterone system inhibition