Antihypertensive treatment guided by genetics: PEARL-HT, the randomized proof-of-concept trial comparing rostafuroxin with losartan.

We compared a standard antihypertensive losartan treatment with a pharmacogenomics-guided rostafuroxin treatment in never-treated Caucasian and Chinese patients with primary hypertension. Rostafuroxin is a digitoxigenin derivative that selectively disrupts the binding to the cSrc-SH2 domain of mutant α-adducin and of the ouabain-activated Na-K pump at 10-11 M. Of 902 patients screened, 172 were enrolled in Italy and 107 in Taiwan. After stratification for country and genetic background, patients were randomized to rostafuroxin or losartan, being the difference in the fall in office systolic blood pressure (OSBP) after 2-month treatment the primary endpoint. Three pharmacogenomic profiles (P) were examined, considering: P1, adding to the gene variants included in the subsequent P2, the variants detected by post-hoc analysis of a previous trial; P2, variants of genes encoding enzymes for endogenous ouabain (EO) synthesis (LSS and HSD3B1), EO transport (MDR1/ABCB1), adducin (ADD1 and ADD3); P3, variants of the LSS gene only. In Caucasians, the group differences (rostafuroxin 50 µg minus losartan 50 mg in OSBP mmHg) were significant both in P2 adjusted for genetic heterogeneity (P2a) and P3 LSS rs2254524 AA [9.8 (0.6-19.0), P = 0.038 and 13.4 (25.4-2.5), P = 0.031, respectively]. In human H295R cells transfected with LSS A and LSS C variants, the EO production was greater in the former (P = 0.038); this difference was abolished by rostafuroxin at 10-11 M. Chinese patients had a similar drop in OSBP to Caucasians with losartan but no change in OSBP with rostafuroxin. These results show that genetics may guide drug treatment for primary hypertension in Caucasians.

Management of dyslipidaemia in patients with chronic kidney disease: a position paper endorsed by the Italian Society of Nephrology.

Chronic kidney disease (CKD) represents a major public health issue worldwide and entails a high burden of cardiovascular events and mortality. Dyslipidaemia is common in patients with CKD and it is characterized by a highly atherogenic profile with relatively low levels of HDL-cholesterol and high levels of triglyceride and oxidized LDL-cholesterol. Overall, current literature indicates that lowering LDL-cholesterol is beneficial for preventing major atherosclerotic events in patients with CKD and in kidney transplant recipients while the evidence is less clear in patients on dialysis. Lipid lowering treatment is recommended in all patients with stage 3 CKD or worse, independently of baseline LDL-cholesterol levels. Statin and ezetimibe are the cornerstones in the management of dyslipidaemia in patients with CKD, however alternative and emerging lipid-lowering therapies may acquire a central role in near future. This position paper endorsed by the Italian Society of Nephrology aims at providing useful information on the topic of dyslipidaemia in CKD and at assisting decision making in the management of these patients.

Hypertension in High School Students: Genetic and Environmental Factors: The HYGEF Study.

Hypertension and obesity in the young population are major risk factors for renal and cardiovascular events, which could arise in adulthood. A candidate-gene approach was applied in a cohort observational study, in which we collected data from 2638 high school adolescent students. Participants underwent anthropometric and blood pressure (BP) measurements, as well as saliva and urine sample collection for genomic DNA extraction and renal function evaluation, respectively. We tested whether candidate genes previously implicated in salt-sensitive hypertension in adults impact BP also among adolescents. Since inflammatory mechanisms may be involved in pathophysiology of hypertension and in endothelial dysfunction and atherosclerosis through reactive oxygen species, the baseline urinary excretion of inflammatory and oxidative stress markers in a subgroup of adolescents stratified according to ADD1(alpha adducin) rs4961 genotypes was assessed. Regression analysis of BP values with genetic polymorphisms, highlighted an association with a missense variant of LSS (lanosterol synthase, rs2254524), a gene coding for an enzyme involved in endogenous ouabain synthesis. Higher diastolic and systolic BP were associated with LSS A allele (P=0.011 and P=0.023, respectively). BP resulted associated with 5 more SNPs. The KL (klotho) rs9536314 missense variant was associated with 24 hour urinary Na+ excretion (P=0.0083). Urinary protein tests showed a greater excretion of IL1ß (interleukin 1ß) and interleukin 10 (P<0.0001) in carriers of the ADD1 rs4961 T allele. In conclusion, 3 missense gene variants already implicated in adult hypertension impact BP or Na+ excretion among adolescents, and, together with activated pro-inflammatory pathways, might predispose to early cardiovascular damage.

Body mass index, fat free mass, uric acid, and renal function as blood pressure levels determinants in young adults.

AIM: We assessed some major determinants of blood pressure (BP) in young adulthood to plan a lifestyle changes policy METHODS: A cross sectional survey was held, involving 2373 high school people (age 18-21), measuring BP, body mass index (BMI), waist circumference (WCirc), fat free mass (FFM); alcohol and smoking habits were evaluated by a questionnaire. In a subset of this population (n = 60) uric acid (UA), estimated glomerular filtration rate (eGFR) were also evaluated. RESULTS: Smoking and not alcohol was correlated to systolic blood pressure (SBP) through quartiles (31.7%, 39.1%, 46.5%, 45.5%). Systolic BP was significantly correlated with FFM in the whole population (r = 0.51) as well as in SBP quartiles (r = 0.243, 0.138, 0.118, 0.204). FFM-SBP cluster analysis gave two centroids corresponding to sexes; females n = 998; coordinates (116.4 mmHg, 38.9 kg) and males n = 1068; coordinates (131.3 mmHg, 56.7 kg). In the n = 60 substudy a multiple linear regression model (multiple R = 0.741) with SBP as dependent variable and UA, FFM, BMI, eGFR as explicative ones, only UA (ß coefficent = 0.363, partial r = 0.240, P < 0.01) was the determinant of BP particularly in men. Moreover in the same group we found an inverse relationship between eGFR (albeit always in the normal range) and UA, as well as for women (r = -0.54, P < 0.01) and men (r = -0.43, P < 0.01) analyzed separately. CONCLUSIONS: A significant correlation exists between BP and FFM; UA has proven to be the most important SBP determinant. At variance with paediatric age UA was negatively correlated with renal function. Dietary intervention on UA and alcohol habits in young adults seems advisable to prevent hypertension.

[Lipid metabolism abnormalities in Chronic Kidney Disease]. / Le alterazioni del metabolismo lipidico nella malattia renale cronica.

Regardless of the etiology of renal disease, patients with chronic kidney disease (CKD) develop profound qualitative and quantitative lipoprotein metabolism abnormalities because of the presence of alterations in apolipoproteins, lipid transfer proteins, lipolytic enzymes, and lipoprotein receptors from the earlier stages of the disease. As renal function deteriorates, triglyceride concentrations increase and high-density lipoprotein cholesterol (HDL) concentrations decline, while levels of low- density lipoprotein (LDL) cholesterol remain in the normal range or become slightly decreased. Meanwhile, there is a progressive accumulation of the more atherogenic small dense LDL particles. In stages 4 and 5 of CKD, there is decreased concentration of apolipoprotein A-containing lipoproteins, and increased concentrations of triglyceride-rich apolipoprotein B-containing lipoproteins. Patients with nephrotic syndrome and preserved glomerular filtration rate show a higher atherogenic profile, with markedly elevated plasma cholesterol, triglyceride concentrations, and increased very low (VLDL) and low density lipoprotein (LDL), intermediate density lipoprotein (IDL) and lipoprotein(a) levels. Depressed plasma HDL cholesterol concentrations are also commonly observed in patients with nephrotic syndrome. Unless nephrotic syndrome is present, lipid abnormalities are not commonly observed when the lipid profile is measured using standard quantitative methods. In particular, total and LDL cholesterol, the most common lipid parameters used to stratify the cardiovascular risk and assess the effect of treatment with statins, are usually normal and often low. However, there is evidence that some alterations of the qualitative profile of lipoprotein are characteristic of chronic kidney disease, and probably contribute to the high rate of atherosclerotic events observed in these patients. These qualitative abnormalities include increased levels of VLDL and IDL cholesterol, small dense and oxidized LDL particles and lipoprotein(a). Moreover, HDL cholesterol is usually low and dysfunctional, not acting as protective, but paradoxically as proatherogenic particles. The lipid profile of CKD shows similar features to the metabolic syndrome and type 2 diabetes, conditions well known to predispose to kidney disease, which in turn aggravates insulin resistance and promotes atherogenic dyslipidemia.

The renal effects of mineralocorticoid receptor antagonists.

Beyond its well known classic effects on renal water and electrolytes metabolism, an increasing amount of experimental and clinical evidence suggests that aldosterone contributes to the pathogenesis and progression of kidney disease. The binding of aldosterone on epithelial and non-epithelial cells of the kidney induces many deleterious effects, such as podocyte apoptosis and injury, mesangial cell proliferation and deformability and tubulointerstitial inflammation, finally resulting in glomerular fibrosis and sclerosis. Moreover, aldosterone acting by fast non-genomic mechanisms, may induce other potential deleterious effects on kidney function and structure. Indeed, many experimental studies have shown that aldosterone participates to the progression of kidney disease through hemodynamic and direct cellular actions and that antagonists of aldosterone may retard the progression of kidney disease, independently of effects on blood pressure. Therefore, blockade of the aldosterone pathway may prove to be a beneficial therapy for kidney disease. In this brief review we summarize the reported data that support an independent role of aldosterone in inducing kidney damage both in human and experimental models, and interventional studies that highlight how strategies aimed to antagonize its action may favorably modify the progressive decline of renal function in patient with kidney disease and in patients with extrarenal disease frequently associated with kidney function impairment.

A pharmacoeconomic analysis of phosphate binders cost-effectiveness in the RISCAVID study.

BACKGROUND: A pharmacoeconomic analysis of the RISCAVID database aimed at assessing the cost effectiveness of phosphate binders in preventing CV mortality and morbidity over 7 years was performed. METHODS: Morbid or fatal events occurring in 750 chronic HD patients were recorded. Statistical analysis evaluated the distribution of variables and the effect of sevelamer on survival. A cost-effectiveness evaluation was performed using a probabilistic model based on a Markov chain. RESULTS: Multivariate analysis showed that treatment with sevelamer was associated with a reduced stroke incidence by 52% (p = 0.04) and reduced levels of C-reactive protein (p < 0.01). Cost-effectiveness evaluation evidenced a 33% decrease in hospital-days for patients treated with sevelamer, with and without comorbidities compared to patients undergoing calcium binders treatment. CONCLUSION: Treatment with sevelamer was associated with a reduced risk of stroke in HD patients, with a clear saving on disease-related costs for the Italian National Healthcare System.

Viral contamination of aerosol and surfaces through toilet use in health care and other settings.

BACKGROUND: The airborne spreading of enteric viruses can occur through the aerosol and droplets produced by toilet flushing. These can contaminate the surrounding environment, but few data exist to estimate the risk of exposure and infection. For this reason environmental monitoring of air and selected surfaces was carried out in 2 toilets of an office building and in 3 toilets of a hospital before and after cleaning operations. METHODS: To reveal the presence of norovirus, enterovirus, rhinovirus, human rotavirus, and Torque teno virus and to quantify human adenovirus and bacteria counts, molecular and cultural methods were used. RESULTS: On the whole, viruses were detected on 78% of surfaces and in 81% of aerosol. Among the researched viruses, only human adenovirus and Torque teno virus were found in both surface and air samples. In several cases the same adenovirus strain was concurrently found in all matrices. Bacterial counts were unrelated to viral presence and cleaning did not seem to substantially reduce contamination. CONCLUSIONS: The data collected in our study confirm that toilets are an important source of viral contamination, mainly in health care settings, where disinfection can have a crucial role in preventing virus spread.

[Statins and kidney disease]. / Statine e rene.

The prevalence of chronic kidney disease (CKD) is increasing worldwide. This clinical and social problem is mainly related to the ongoing epidemic of obesity and metabolic syndrome resulting in hypertension and diabetes mellitus. CKD is a well-recognized risk multiplier for the development of cardiovascular disease (CVD), and it is widely known that CVD is the leading cause of morbidity and mortality in patients with CKD. Lipid metabolism abnormalities are commonly associated with CKD. These consist of increased levels of low-density lipoproteins (LDL), triglycerides, very-low-density lipoproteins (VLDL) and lipoprotein(a), and reduced levels of HDL cholesterol. Lipid abnormalities contribute to cardiovascular morbidity and mortality in CKD patients. Some evidence also suggests that dyslipidemia may contribute to the progression of renal disease associated with type 1 and type 2 diabetic as well as non-diabetic renal disease. In the general population, HMG-CoA reductase inhibitors (statins) reduce the cardiovascular risk and prevent CVD. Similar data from secondary analyses of CKD subgroups of larger prospective trials using statins suggest a beneficial effect on cardiovascular outcomes and - albeit with more conflicting evidence - the progression of renal disease. Statins reduce blood levels of LDL cholesterol but also have multiple effects above and beyond cholesterol lowering, including direct effects on vascular tissue, kidney, bone, and glucose metabolism. The evidence linking dyslipidemia management with statins to cardiovascular disease and the decline in renal function in CKD patients will be presented in this review.

Do HMG-CoA reductase inhibitors improve kidney function? The saga continues.

Several reviews have addressed the role of dyslipidemia in renal injury and the potential renal protective effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins). Experimental evidence in animals strongly supports the concept that statins may be renal protective. However, data in humans are scanty and contradictory. A recent controlled study using rosuvastatin has cast some doubts on the renal protective effect of this drug. This article reviews the available evidence pro and con the renal protective effects of statins in human subjects.

Statins and lipid-lowering strategies in cardiorenal patients.

The prevalence of chronic kidney disease (CKD) is increasing alarmingly mainly as a result of an ongoing epidemic of obesity, metabolic syndrome, and diabetes mellitus. CKD is a well-recognized risk multiplier for development of cardiovascular disease (CVD), and it is widely known that CVD is the leading cause of morbidity and mortality in patients with CKD. Cardiovascular (CV) morbidity and mortality is significantly increased along the continuum of CKD, and it is more than 10 times higher in end-stage renal disease populations than in the general population. Lipid metabolism is profoundly disturbed in CKD, and there is a gradual shift to the uremic lipid profile as kidney function deteriorates, which is further modified by the presence of comorbidities such as diabetes and obesity. Apart from quantitative differences, major qualitative changes in lipoproteins can be observed, such as oxidization and modification to small and dense low-density lipoprotein (LDL), which render the particles more atherogenic. It has been noted that these abnormalities contribute to the development of CV events, and they may lead to the progression of CKD. Lipid-lowering treatment with statins in the general population has achieved important benefits both in reducing CV risk and in the prevention of CVD. Similarly, data from secondary analyses of CKD subgroups of larger prospective trials using statins also suggest an important benefit on CV outcomes and, with more conflicting evidence, on the progression of kidney disease. Preliminary results from a large randomized controlled trial of lipid-lowering therapy in CKD confirm similar benefits of treatment for dyslipidemia in patients with CKD and ESRD. The safety profile of lipid- lowering therapy with statins in CKD is not different from that observed in people with normal renal function. Hence, lipid- lowering therapy with statins should be part of the standard treatment of patients with CKD.

Anaemia and resistance to erythropoiesis-stimulating agents as prognostic factors in haemodialysis patients: results from the RISCAVID study.

BACKGROUND: Resistance to erythropoiesis-stimulating agents (ESAs) is often associated with chronic inflammation. Here, we investigated how anaemia, ESA resistance and the plasma levels of biological markers of inflammation could influence all-cause and cardiovascular disease morbidity and mortality. METHODS: Seven hundred and fifty-three haemodialysis (HD) patients (mean age 66 ± 14.2 years, mean dialytic age 70 ± 77 months and diabetes 18.8%) were enrolled and followed-up for 36 months. Demographic, clinical and laboratory data, co-morbidity conditions, administered drugs, all-cause mortality and fatal/non-fatal cardiovascular (CV) events were recorded. We measured ESA resistance index, C-reactive protein (CRP) and interleukin-6 (IL-6). RESULTS: Six hundred and fifty-one patients (86.4%) received ESAs. Patients with haemoglobin level <11 g/dL (n = 225) showed increased risk of CV [relative risk (RR) 1.415, 95% confidence interval (CI) 1.046-1.914] and overall mortality (RR 1.897, 95% CI 1.423-2.530) versus patients with haemoglobin levels >11 g/dL. ESA resistance values categorized into quartiles (Quartile I <5.6, Quartile II 5.7-9.6, Quartile III 9.7-15.4 and Quartile IV >15.4) correlated with all-cause mortality and fatal/non-fatal CV events (RR 1.97, 95% CI 1.392-2.786; RR 1.619, 95% CI 1.123-2.332, respectively). Furthermore, albumin was significantly reduced versus reference patients and correlated with all-cause mortality and CV events; CRP levels were higher in hyporesponders (Quartile IV) (P < 0.001) and predicted all-cause mortality and CV events. IL-6 but not CRP was a strong predictor of ESA resistance. CONCLUSIONS: ESA responsiveness can be considered a strong prognostic factor in HD patients and seems to be tightly related to protein-energy wasting and inflammation.

Soluble CD40 ligand is predictive of combined cardiovascular morbidity and mortality in patients on haemodialysis at a relatively short-term follow-up.

BACKGROUND: We tested the hypothesis that soluble CD40 ligand (sCD40L), a biomarker of proatherogenic inflammation, may be predictive of cardiovascular (CV) events in a subgroup of patients from the RISCAVID study, an observational and prospective study in patients on haemodialysis (HD). METHODS: Plasma sCD40L levels were assessed at the time of the enrollment in 300 HD patients (mean age: 65 ± 15 years), recruited in five different centres. During a follow-up of 24 months, overall mortality, CV mortality and CV major nonfatal events (acute myocardial infarction, congestive heart failure and stroke) were registered. Cox proportional hazards regression assessed adjusted differences in CV morbidity and mortality risk. RESULTS: Stratifying patients according to plasma sCD40L levels in those with levels lower or equal to (sCD40L-) and greater than (sCD40L+) the median value of 7.6 ng/mL, no significant difference was observed at baseline between the two groups in age, gender, blood pressure values and previous CV events. At 24-month follow-up, a significant (P < 0.01) lower incidence of the combined end point of CV morbidity and mortality was observed in the sCD40L- group (29%) as compared to the sCD40L+ group (36%). In the multivariate Cox proportional hazards regression model, the presence of sCD40L above the median value is associated with a significant increase in the risk of CV morbidity and mortality (hazard ratio: 1.61, 95% confidence interval 1.03-3.11). CONCLUSIONS: These observational results support the prognostic value of sCD40L in end-stage renal disease, thus providing a useful tool to better stratify CV prognosis in these patients.

A vitamin E-coated polysulfone membrane reduces serum levels of inflammatory markers and resistance to erythropoietin-stimulating agents in hemodialysis patients: results of a randomized cross-over multicenter trial.

BACKGROUND: Oxidative stress is prevalent in dialysis patients and has been implicated in the pathogenesis of cardiovascular disease and anemia. Vitamin E is a fat-soluble antioxidant that plays a central role in reducing lipid peroxidation and inhibiting the generation of reactive oxygen species. The aim of this cross-over randomized study was to compare the effects of a vitamin E-coated polysulfone (Vit E PS) membrane and a non-vitamin E-coated polysulfone (PS) membrane on inflammatory markers and resistance to erythropoietin-stimulating agents (ESAs). METHODS: After a 1-month run-in period of standard bicarbonate dialysis with a synthetic membrane, 62 patients of both genders, and older than 18 years, dialysis vintage 48 ± 27 months, BMI 22 ± 3 (from 13 different dialysis units) were randomized (A-B or B-A) in a cross-over design to Vit E PS (treatment A) and to PS (treatment B) both for 6 months. C-reactive protein (CRP) and interleukin-6 (IL-6) concentrations were determined by a sandwich enzyme immunoassay at baseline and every 2 months; red blood cell count, ESA dose and ESA resistance index (ERI) were assessed monthly. RESULTS: Hemoglobin (Hb) levels significantly increased in the Vit E PS group from 11.1 ± 0.6 g/dl at baseline to 11.5 ± 0.7 at 6 months (p < 0.001) and remained unchanged in the PS group. Although ESA dosage remained stable during the observation periods in both groups, ERI was significantly reduced in the Vit E PS group from 10.3 ± 2.2 IU-dl/kg/g Hb week at baseline to 9.2 ± 1.7 at 6 months (p < 0.001). No significant variation of ERI was observed in the PS group. A significant reduction in plasma CRP and IL-6 levels was observed in the Vit E PS group: CRP from 6.7 ± 4.8 to 4.8 ± 2.2 mg/l (p < 0.001) and IL-6 from 12.1 ± 1.4 to 7.5 ± 0.4 pg/ml (p < 0.05). In the PS group, CRP varied from 6.2 ± 4.0 to 6.4 ± 3.7, and IL-6 from 10.6 ± 2.1 to 9.6 ± 3.5 (p = n.s.). CONCLUSIONS: Treatment with Vit E PS membranes seems to lead to a reduction in ESA dosage in HD patients; in addition, a low chronic inflammatory response may contribute to a sparing effect on exogenous ESA requirements.

Management of secondary hyperparathyroidism in Italy: results of the Italian FARO survey.

AIMS: In recent years, treatment options for secondary hyperparathyroidism (SHPT) have increased (e.g., paricalcitol, calcimimetics). To determine the impact these new treatments have on achieving K/DOQI targets, an observational, prospective survey was undertaken. METHODS: Four 6-month time-spaced surveys of 2,637 patients in 28 Italian dialysis units were performed. Patient demographic information; use of vitamin D or calcimimetics; and changes in parathyroid hormone (PTH), calcium (Ca) and phosphate (P) levels were evaluated. RESULTS: Over the course of the survey, use of calcitriol decreased (from 62.1% at baseline to 44.5% at month 18; p<0.001), while use of paricalcitol (from 19.9% to 36.9%; p<0.001) and calcimimetics (from 6.4% to 10.8%; p<0.001) increased. This was associated with a decrease in mean PTH values (from 310.3 ± 292.4 pg/mL at baseline to 279.5 ± 250.1 pg/mL at month 18; p=0.0002), while mean Ca and P remained steady. The percentage of patients achieving K/DOQI ranges for PTH (from 26.8% at baseline to 32.0% at month 18, p<0.001), Ca (from 50.4% at baseline to 55.9% at month 18, p<0.001) and the 3 targets combined (PTH, Ca and P; from 8.8% at baseline to 11.5% at month 18, p=0.003) significantly increased (p<0.05). Despite the introduction of newer agents, two thirds of patients did not achieve target levels. CONCLUSIONS: Increased awareness and newer treatment options for chronic kidney disease patients with SHPT have changed treatment policy and number of patients achieving K/DOQI target levels in Italy. However, the majority of patients did not meet the target ranges, suggesting that new drugs and strategies are still warranted for optimal management of SHPT in chronic kidney disease.

Impact of calcium, phosphate, PTH abnormalities and management on mortality in hemodialysis: results from the RISCAVID study.

BACKGROUND: Despite substantial progress in medical care, the mortality rate remains unacceptably high in dialysis patients. Evidence suggests that bone mineral dismetabolism (CKD-MBD) might contribute to this burden of death. However, to date only a few papers have investigated the clinical relevance of serum mineral derangements and the impact of different therapeutic strategies on mortality in a homogeneous cohort of south European dialysis patients. METHODS: The RISCAVID study was a prospective, observational study in which all patients receiving hemodialysis (HD) in the north-western region of Toscany in June 2004 were enrolled (N=757) and followed up for 24 months. RESULTS: At study entry, only 71 (9%) patients of the entire study cohort exhibited an optimal control of serum phosphorous (Pi), calcium (Ca), calciumX-phosphorous product (CAXPi) and intact parathyroidhormone (iPTH) according to the Kidney Disease Outcomes Quality Initiative (K/DOQI) clinical guidelines. Despite a similar prevalence, the severity of CKD-MBD appeared different to the results reported in the USA. Interestingly, none of the serum biomarkers or number of serum biomarkers within KDOQI targets was independently associated with all-cause and cardiovascular (CV) mortality. Among treatments, Sevelamer was the only drug independently associated with lower all-cause and cardiovascular mortality (p<0.001). CONCLUSION: The RISCAVID study highlights the difficulty of controlling bone mineral metabolism in HD patients and lends support to the hypothesis that a carefully chosen phosphate binder might impact survival in HD patients.

Intensive versus conventional therapy to slow the progression of idiopathic glomerular diseases.

BACKGROUND: Chronic kidney disease (CKD) caused by idiopathic glomerular diseases usually is progressive. Inhibition of the renin-angiotensin system (RAS) retards, but does not abrogate, CKD progression. Statins and spironolactone may decrease the rate of CKD progression independently or in addition to RAS inhibition. STUDY DESIGN: Randomized open-label study. SETTING & PARTICIPANTS: We recruited 128 patients (82 men and 46 women) with a clinical diagnosis of idiopathic chronic glomerulonephritis and estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m(2) (range, 36-102 mL/min/1.73 m(2)), and urine protein-creatinine ratio ranging from 1.1-5.2 g/g. INTERVENTION: Intensive therapy (a combination of RAS inhibitors [angiotensin-converting enzyme [ACE] inhibitors plus angiotensin receptor blockers [ARBs] plus a high-dose statin and spironolactone) versus conventional therapy (a regimen based on ACE inhibitors with a low-dose statin). OUTCOMES: Changes in eGFR, proteinuria, and adverse events after 3 years of therapy. RESULTS: With intensive therapy, urine protein-creatinine ratio decreased from 2.65 (range, 1.1-5.2) to 0.45 (0.14-1.51) g/g (P < 0.001) and eGFR did not significantly change over time (64.6 +/- 2.1 vs 62.9 +/- 2.9 mL/min/1.73 m(2)). With conventional therapy, urine protein-creatinine ratio decreased from 2.60 (range, 1.32-5.4) to 1.23 (0.36-3.42) g/g (P < 0.001) and eGFR decreased from 62.5 +/- 1.7 to 55.8 +/- 1.9 mL/min/1.73 m(2) (P < 0.001). Comparison of the decreases in proteinuria and GFR between intensive versus conventional therapy was significantly different starting in the 1st and 12th months, respectively. Systolic blood pressure was lower with intensive than conventional therapy (113.5 +/- 1.4 vs 122.7 +/- 1.2 mm Hg; P < 0.01). We found an inverse relationship between percentage of decrease in proteinuria and change in eGFR (P < 0.001). Patients on intensive therapy were more likely to develop adverse events, such as hyperkalemia (9 vs 3 patients in the conventional therapy group) and discontinue therapy (15 vs 8 patients in the conventional therapy group). LIMITATIONS: Open-label design. CONCLUSIONS: A more intensive therapy that includes a combination of ACE inhibitors and ARBs plus high-dose statins and spironolactone may retard CKD progression more effectively than conventional therapy based on ACE inhibitors plus low-dose statin, but may lead to more adverse effects and discontinuation of therapy.

Angiotensin receptor blocker telmisartan improves insulin sensitivity in peritoneal dialysis patients.

BACKGROUND: Insulin resistance (IR) is common among patients on dialysis and is worse among patients on peritoneal dialysis (PD) than among patients on hemodialysis. In this study we tested the hypothesis that administration of telmisartan, an angiotensin II type 1 receptor antagonist, might improve insulin sensitivity in patients on PD. METHOD: This was a crossover study of 30 nondiabetic patients with end-stage renal disease being treated with PD. Group A patients (n = 15) received telmisartan and other antihypertensive drugs for 4 months, followed by 4 months without telmisartan. Group B patients (n = 15) received their usual treatment for 4 months, followed by 4 months of treatment with telmisartan. Blood glucose and serum insulin levels were monitored and homeostasis model assessment method for IR (HOMA-IR) was calculated. RESULTS: Treatment with telmisartan had no significant impact on serum glucose, potassium, and bicarbonate levels. However, telmisartan significantly reduced serum insulin levels and the HOMA index in groups A and B. CONCLUSION: This study demonstrated that telmisartan, an angiotensin receptor type 1 antagonist, may effectively improve insulin sensitivity as measured by HOMA in patients treated with PD.

Chronic inflammation and mortality in haemodialysis: effect of different renal replacement therapies. Results from the RISCAVID study.

BACKGROUND: The 'RISchio CArdiovascolare nei pazienti afferenti all' Area Vasta In Dialisi' (RISCAVID) study is an observational and prospective trial including the whole chronic haemodialysis (HD) population in the northwest part of Tuscany (1.235 million people). The aim of the study was to elucidate the relevance of traditional and non-traditional risk factors of mortality and morbidity in HD patients as well as the impact of different HD modalities. METHODS: A total of 757 HD patients (mean age 66 +/- 14 years, mean dialytic age 70 +/- 76 months, diabetes 19%) were prospectively followed up for 30 months and all-cause mortality, cardiovascular (CV) mortality and non-fatal CV events (acute myocardial infarction and stroke) were registered. At the time of the enrolment, demographic, clinical and laboratory data of the whole population were entered into a centralized database. Serum albumin, high-sensitive C-reactive protein (CRP), interleukin-6 (IL-6) and interleukin-8 (IL-8) were centrally determined at the start of the study. Patients were stratified into three groups according to the HD modality: standard bicarbonate HD (BHD) (n = 424), haemodiafiltration (HDF) with sterile bags (n = 204) and online HDF (n = 129). The Cox proportional hazards regression assessed adjusted differences in CV morbidity and mortality risk; a multivariate analysis was also performed. RESULTS: All-cause and CV mortality was 12.9%/year and 5.9%/year, respectively. Patients with combined high levels of CRP and pro-inflammatory cytokines showed an increased risk for CV (RR 1.9, P < 0.001) and all-cause mortality (RR 2.57, P < 0.001). Multivariate analysis adjusted for comorbidity and demographic showed CRP as the most powerful mortality predictor (P < 0.001) followed by IL-6. The Cox proportional hazards regression assessed that online HDF and HDF patients had a significantly increased adjusted cumulative survival than BHD (P < 0.01). CONCLUSIONS: Data at 30 months from this study showed the synergic effect of CRP and pro-inflammatory cytokines as the strong predictors of all-cause and CV mortality. HDF was associated with an improved cumulative survival independent of the dialysis dose.

Increased cardiovascular events in hypertensive patients with insulin resistance: a 13-year follow-up.

Insulin resistance (IR) is commonly associated with other cardiovascular risk factors and is considered an independent risk factor for cardiovascular disease and events. The hyperinsulinemic euglycemic clamp technique is considered the gold standard for evaluating IR, but this technique is cumbersome and not easily applicable in large studies. Therefore, there are no long-term follow-up published studies on the relationship between IR determined by this technique and cardiovascular outcome. Thirteen years ago we performed a hyperinsulinemic euglycemic clamp in 31 hypertensive patients, 16 of whom manifested IR and 15 had normal insulin sensitivity. Thirteen years later we were able to re-evaluate or obtain medical records for all these patients. Over these years, 11 of the 16 insulin resistant patients developed cardiovascular disease and events, including two cardiovascular deaths, two myocardial infarctions, one angina pectoris, one peripheral vascular disease, and five carotid plaques or stenosis. Moreover, two patients developed new onset diabetes, one proteinuria and two impaired kidney function. Among insulin-sensitive patients, one developed peripheral vascular disease, one new onset diabetes and one proteinuria. In conclusion, this is the first longitudinal study of the relationship between insulin resistance, measured by the hyperinsulinemic euglycemic clamp and cardiovascular disease and events in a small cohort of patients with essential hypertension. The data suggest that hypertensive patients with IR are at greater risk of developing cardiovascular disease and events than hypertensive patients with normal insulin sensitivity.