Non-Haemodynamic Mechanisms Underlying Hypertension-Associated Damage in Target Kidney Components.

Arterial hypertension (AH) is a global challenge that greatly impacts cardiovascular morbidity and mortality worldwide. AH is a major risk factor for the development and progression of kidney disease. Several antihypertensive treatment options are already available to counteract the progression of kidney disease. Despite the implementation of the clinical use of renin-angiotensin aldosterone system (RAAS) inhibitors, gliflozins, endothelin receptor antagonists, and their combination, the kidney damage associated with AH is far from being resolved. Fortunately, recent studies on the molecular mechanisms of AH-induced kidney damage have identified novel potential therapeutic targets. Several pathophysiologic pathways have been shown to play a key role in AH-induced kidney damage, including inappropriate tissue activation of the RAAS and immunity system, leading to oxidative stress and inflammation. Moreover, the intracellular effects of increased uric acid and cell phenotype transition showed their link with changes in kidney structure in the early phase of AH. Emerging therapies targeting novel disease mechanisms could provide powerful approaches for hypertensive nephropathy management in the future. In this review, we would like to focus on the interactions of pathways linking the molecular consequences of AH to kidney damage, suggesting how old and new therapies could aim to protect the kidney.

Uric acid lowering for slowing CKD progression after the CKD-FIX trial: a solved question or still a dilemma?

Hyperuricemia has been associated with several cardiovascular risk factors and is a well-known predictor of kidney disease. In vitro studies as well as animal models highlighted a role for uric acid in the development and progression of haemodynamic and tissue damage at the renal level leading to glomerular and tubulointerstitial abnormalities. Urate-lowering treatment, especially by xanthine oxidase inhibitors, has been proposed in order to improve kidney outcomes. However, recent randomized controlled trials failed to demonstrate a beneficial effect of allopurinol or febuxostat on renal disease, casting doubts on the role of this therapeutical approach to improve nephroprotection. We provide a critical overview of current literature on this topic and offer a possible interpretation of results from recent intervention trials with urate-lowering treatment on renal outcomes.

Association of uric acid with kidney function and albuminuria: the Uric Acid Right for heArt Health (URRAH) Project.

BACKGROUND: Hyperuricemia is commonly observed in patients with chronic kidney disease (CKD). However, a better understanding of the relationship among uric acid (UA) values, glomerular filtration rate (GFR) and albuminuria may shed light on the mechanisms underlying the excess of cardiovascular mortality associated with both chronic kidney disease and hyperuricemia and lead to better risk stratification. Our main goal was to study the relationships between serum uric acid and kidney disease measures (namely estimated GFR [eGFR] and albuminuria) in a large cohort of individuals at cardiovascular risk from the URic acid Right for heArt Health (URRAH) Project database. METHODS: Clinical data of 26,971 individuals were analyzed. Factors associated with the presence of hyperuricemia defined on the basis of previously determined URRAH cutoffs for cardiovascular and all-cause mortality were evaluated through multivariate analysis. Chronic kidney disease was defined as eGFR < 60 ml/min per 1.73 m2 and/or abnormal urinary albumin excretion diagnosed as: (i) microalbuminuria if urinary albumin concentration was > 30 and ≤ 300 mg/L, or if urinary albumin-to-creatinine ratio (ACR) was > 3.4 mg/mmol and ≤ 34 mg/mmol; (ii) macroalbuminuria if urinary albumin concentration was > 300 mg/L, or if ACR was > 34 mg/mmol. RESULTS: Mean age was 58 ± 15 years (51% males, 62% with hypertension and 12% with diabetes), mean eGFR was 81 ml/min per 1.73m22with a prevalence of eGFR < 60 and micro- or macroalbuminuria of 16, 15 and 4%, respectively. Serum uric acid showed a trend towards higher values along with decreasing renal function. Both the prevalence of gout and the frequency of allopurinol use increased significantly with the reduction of eGFR and the increase in albuminuria. Hyperuricemia was independently related to male gender, eGFR strata, and signs of insulin resistance such as body mass index (BMI) and triglycerides. CONCLUSIONS: The lower the eGFR the higher the prevalence of hyperuricemia and gout. In subjects with eGFR < 60 ml/min the occurrence of hyperuricemia is about 10 times higher than in those with eGFR > 90 ml/min. The percentage of individuals treated with allopurinol was below 2% when GFR was above 60 ml/min, it increased to 20% in the presence of CKD 3b and rose further to 35% in individuals with macroalbuminuria.

Serum Uric Acid and Kidney Disease Measures Independently Predict Cardiovascular and Total Mortality: The Uric Acid Right for Heart Health (URRAH) Project.

Background: Serum uric acid predicts the onset and progression of kidney disease, and the occurrence of cardiovascular and all-cause mortality. Nevertheless, it is unclear which is the appropriate definition of hyperuricemia in presence of chronic kidney disease (CKD). Our goal was to study the independent impact of uric acid and CKD on mortality. Methods: We retrospectively investigated 21,963 patients from the URRAH study database. Hyperuricemia was defined on the basis of outcome specific cut-offs separately identified by ROC curves according to eGFR strata. The primary endpoints were cardiovascular and all-cause mortality. Results: After a mean follow-up of 9.8 year, there were 1,582 (7.20%) cardiovascular events and 3,130 (14.25%) deaths for all causes. The incidence of cardiovascular and all-cause mortality increased in parallel with reduction of eGFR strata and with progressively higher uric acid quartiles. During 215,618 person-years of follow-up, the incidence rate for cardiovascular mortality, stratified based on eGFR (>90, between 60 and 90 and <60 ml/min) was significantly higher in patients with hyperuricemia and albuminuria (3.8, 22.1 and 19.1, respectively) as compared to those with only one risk factor or none (0.4, 2.8 and 3.1, respectively). Serum uric acid and eGFR significantly interact in determining cardiovascular and all-cause mortality. For each SUA increase of 1 mg/dl the risk for mortality increased by 10% even after adjustment for potential confounding factors included eGFR and the presence of albuminuria. Conclusions: hyperuricemia is a risk factor for cardiovascular and all-cause mortality additively to eGFR strata and albuminuria, in patients at cardiovascular risk.

SGLT2is and Renal Protection: From Biological Mechanisms to Real-World Clinical Benefits.

In recent years, following the publication of results from several RCTs, first on cardiovascular and more recently on renal outcomes, SGLT2is have become the standard of care to prevent diabetic kidney disease and slow its progression. This narrative review focuses on biological mechanisms, both renal and extrarenal, underlying kidney protection with SGLT2is. Furthermore, data from cardiovascular as well as renal outcome trials, mostly conducted in diabetic patients, are presented and discussed to provide an overview of current uses as well as the future therapeutic potential of these drugs.

Treating Hyperuricemia: The Last Word Hasn't Been Said Yet.

Gout as well as asymptomatic hyperuricemia have been associated with several traditional cardiovascular risk factors and chronic kidney disease. Both in vitro studies and animal models support a role for uric acid mediating both hemodynamic and tissue toxicity leading to glomerular and tubule-interstitial damage, respectively. Nevertheless, two recent well designed and carried out trials failed to show the benefit of allopurinol treatment on kidney outcomes, casting doubts on expectations of renal protection by the use of urate lowering treatment. With the aim of providing possible explanations for the lack of effect of urate lowering treatment on chronic kidney disease progression, we will critically review results from all available randomized controlled trials comparing a urate-lowering agent with placebo or no study medication for at least 12 months and report renal clinical outcomes.

Blood pressure reduction and RAAS inhibition in diabetic kidney disease: therapeutic potentials and limitations.

Diabetic kidney disease (DKD) affects approximately one-third of patients with diabetes and taking into consideration the high cardiovascular risk burden associated to this condition a multifactorial therapeutic approach is traditionally recommended, in which glucose and blood pressure control play a central role. The inhibition of renin-angiotensin-aldosterone RAAS system represent traditionally the cornerstone of DKD. Clinical outcome trials have demonstrated clinical significant benefit in slowing nephropathy progression mainly in the presence of albuminuria. Thus, international guidelines mandate their use in such patients. Given the central role of RAAS activity in the pathogenesis and progression of renal and cardiovascular damage, a more profound inhibition of the system by the use of multiple agents has been proposed in the past, especially in the presence of proteinuria, however clinical trials have failed to confirm the usefulness of this therapeutic approach. Furthermore, whether strict blood pressure control and pharmacologic RAAS inhibition entails a favorable renal outcome in non-albuminuric patients is at present unclear. This aspect is becoming an important issue in the management of DKD since nonalbuminuric DKD is currently the prevailing presenting phenotype. For these reasons it would be advisable that blood pressure management should be tailored in each subject on the basis of the renal phenotype as well as related comorbidities. This article reviews the current literature and discusses potentials and limitation of targeting the RAAS in order to provide the greatest renal protection in DKD.

Long-term blood pressure variability, incidence of hypertension and changes in renal function in type 2 diabetes.

OBJECTIVES: Long-term visit-to-visit SBP variability (VVV) predicts cerebro-cardiovascular and renal events in patients with hypertension. Whether VVV predicts hypertension and/or chronic kidney disease is currently unknown. We assessed the role of VVV on the development of hypertension and changes in renal function in patients with type 2 diabetes and normal blood pressure (NBP) in a real-life clinical setting. METHODS: Clinical records from 8998 patients with type 2 diabetes, NBP, and normal estimated glomerular filtration rate (eGFR) were analyzed. VVV was measured by SD of the mean SBP recorded in at least four visits during 2 consecutive years before follow-up. Hypertension was defined as SBP at least 140 mmHg and DBP at least 90 mmHg or the presence of antihypertensive treatment. Renal function was defined as worsening of albuminuria status and/or a reduction in eGFR at least 30% from baseline. RESULTS: After a mean follow-up time of 3.5 ±â€Š2.8 years, 3795 patients developed hypertension (12.1 per 100 person-years). An increase of 5 mmHg VVV was associated with a 19% (P < 0.0001) and a 5% (P = 0.008) independent increased risk of developing hypertension and worsening of albuminuria, respectively. We found no association between VVV and eGFR decrease from baseline. Patients with VVV in the upper quartile (>12.8 mmHg) showed a 50% increased risk of developing hypertension (P < 0.0001) and an almost 20% increased risk of worsening albuminuria (P = 0.004) as compared with those in the lower one (<6.9 mmHg). CONCLUSION: Increased VVV independently predicts incident hypertension and albuminuria worsening in type 2 diabetes and NBP.

Fructose and Uric Acid: Major Mediators of Cardiovascular Disease Risk Starting at Pediatric Age.

Recently, there has been a growing interest in epidemiological and clinical studies supporting a pathogenetic role of fructose in cardio-metabolic diseases, especially in children and adolescents. In the present review, we summarize experimental data on the potential biological mechanisms linking fructose and uric acid in the development of insulin resistance, metabolic syndrome, obesity, diabetes, hypertension, non-alcoholic fatty liver disease and chronic renal disease, thereby contributing to an increase in cardiovascular risk at pediatric age.

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.

Uric acid in CKD: has the jury come to the verdict?

Epidemiological studies show that hyperuricemia independently predicts the development of chronic kidney disease (CKD) in individuals with normal kidney function both in the general population and in subjects with diabetes. As a matter of fact, an unfavorable role of uric acid may somewhat be harder to identify in the context of multiple risk factors and pathogenetic mechanisms typical of overt CKD such as proteinuria and high blood pressure. Although the discrepancy in clinical results could mean that urate lowering treatment does not provide a constant benefit in all patients with hyperuricemia and CKD, we believe that the inconsistency in the results from available meta-analysis is mainly due to inadequate sample size, short follow-up times and heterogeneity in study design characterizing the randomized controlled trials included in the analyses. Therefore, available data support the view that hyperuricemia has a damaging impact on kidney function, while preliminary evidence suggests that treatment of so-called asymptomatic hyperuricemia may be helpful to slow or delay the progression of chronic kidney.

Effects of dual inhibition of renin-angiotensin-aldosterone system on cardiovascular and renal outcomes: balancing the risks and the benefits.

Chronic kidney disease is a worldwide health problem often burdened by severe cardiovascular complications. Hypertension represents one of the most important risk factor in affecting cardiovascular profile of chronic kidney disease patients. Since renin-angiotensin-aldosterone system plays a major role in determining cardiovascular outcome, guidelines recommend the use of renin-angiotensin-aldosteron inhibitors in order to control hypertension.

Two-Day ABPM-Derived Indices and Mortality in Hemodialysis Patients.

BACKGROUND: Blood pressure (BP) and arterial stiffness are known cardiovascular risk factors in hemodialysis (HD) patients. This study examines the prognostic significance of 44-hour BP circadian rhythm and ambulatory arterial stiffness index (AASI) in this population. METHODS: A total of 80 HD patients underwent 44-hour ambulatory BP monitoring (ABPM) with a TM-2430 monitor during a standard midweek interdialytic interval and followed up for 4.5 ± 1.7 years. The end point was all-cause mortality. RESULTS: About 76% of participants were hypertensive (40% uncontrolled), 62% were nondippers, and 23% risers during the first interdialytic day, whereas 73% and 44% in the second day, respectively. During follow-up, 31 patients (40%) died. These showed higher pulse pressure (PP) and AASI44 and AASI of the second interdialytic period. The incidence of all-cause mortality was higher in HD patients with AASI44 > median, i.e. >0.54 (interquartile range = 14) (54% vs. 28%, χ 2 = 5.3, P = 0.021) when compared with those with lower AASI44. Second, but not first-day ABPM-derived parameters, namely nondipping (log-rank χ 2 = 6.10, P = 0.0134) or reverse dipping status (log-rank χ 2 = 5.32, P = 0.210) and arterial stiffness index (log-rank χ 2 = 6.61, P = 0.0101) were significantly related to greater mortality. CONCLUSIONS: These findings indicate a strong relationship between arterial stiffness and cardiovascular risk and support a wider use of 44-hour ABPM recording for risk stratification in HD patients.

Impact of CVOTs in primary and secondary prevention of kidney disease.

Type 2 diabetes mellitus is the leading cause of end stage renal disease worldwide. Diabetic kidney disease, whose main clinical manifestations are albuminuria and decline of glomerular filtration rate, affects up to 40% of patients. Sodium Glucose cotransporter-2 inhibitors (SGLT2-is) and Glucagon-like peptide-1 receptor agonists (GLP-1ras) are new classes of anti-hyperglycemic drugs which have demonstrated to improve renal outcome. Renal benefits of both SGLT2-is and GLP-1ras are acknowledged from data of large randomized phase III clinical trials conducted to assess their cardiovascular safety. In this review, we will focus on renal results of major cardiovascular outcome trials, and we will describe direct and indirect mechanisms through which they confer renal protection.

Antihypertensive Treatment in Diabetic Kidney Disease: The Need for a Patient-Centered Approach.

Diabetic kidney disease affects up to forty percent of patients with diabetes during their lifespan. Prevention and treatment of diabetic kidney disease is currently based on optimal glucose and blood pressure control. Renin-angiotensin aldosterone inhibitors are considered the mainstay treatment for hypertension in diabetic patients, especially in the presence of albuminuria. Whether strict blood pressure reduction entails a favorable renal outcome also in non-albuminuric patients is at present unclear. Results of several clinical trials suggest that an overly aggressive blood pressure reduction, especially in the context of profound pharmacologic inhibition of the renin-angiotensin-aldosterone system may result in a paradoxical worsening of renal function. On the basis of this evidence, it is proposed that blood pressure reduction should be tailored in each individual patient according to renal phenotype.

Chronic Intake of Micrograms of Abscisic Acid Improves Glycemia and Lipidemia in a Human Study and in High-Glucose Fed Mice.

We tested the effect of chronic low-dose abscisic acid (ABA), a phytohormone-regulating human glucose tolerance, on the metabolic parameters that are dysregulated in prediabetes and metabolic syndrome (MS).Ten healthy subjects received 1 µg ABA/Kg body weight (BW)/day as an ABA-rich food supplement: (i) the glycemia profile after a carbohydrate-rich meal, with or without supplement, was compared; (ii) fasting blood glucose (FBG), glycated hemoglobin (HbA1c), total cholesterol (TC), and body mass index (BMI) after 75 days of daily supplementation of a habitual Mediterranean diet were compared with starting values.CD1 mice were fed a high-glucose diet with or without synthetic ABA (1 µg/Kg BW) for 4 months and the same parameters investigated in the human study were compared. The food supplement significantly reduced the area under the curve of glycemia after a carbohydrate-rich meal and FBG, HbA1c, TC, and BMI after chronic treatment. ABA-treated mice showed a significant reduction of HbA1c, TC, and body weight gain compared with untreated controls. The combined results from the human and murine studies allow us to conclude that the observed improvement of the metabolic parameters can be attributed to ABA and to advocate the use of ABA-containing food supplements in prediabetes and/or MS.

Antihypertensive treatment and renal protection: Is there a J-curve relationship?

A bidirectional relationship between hypertension and kidney disease, with one exacerbating the effect of the other, is well established. Elevated blood pressure (BP) is a well-recognized, modifiable risk factor for cardiovascular (CV) disease as well as for development and progression of chronic kidney disease and, therefore, the identification of optimal BP target is a key issue in the management of renal patients. Recent large trials and real life cohort studies have indicated that below a definite BP value renal protection seems to plateau and too low levels may even be associated with a paradoxical increase in renal morbidity, thus reviving the debate about the so called BP -renal function J-curve relationship. Existing evidence supports a systolic target around 130 mm Hg to combine both renal and CV protection and possibly lower levels in the presence of overt proteinuria.

Peripheral artery disease and blood pressure profile abnormalities in hemodialysis patients.

BACKGROUND: Patients undergoing chronic hemodialysis (HD) are at increased risk for peripheral artery disease (PAD). Both ankle-brachial index (ABI) and ambulatory blood pressure monitoring (ABPM) in the interdialytic period have been shown to be strong predictors of all-cause mortality. METHODS: This cross-sectional study investigated the relationship between ABPM profile and ABI in 81 HD patients. ABPM was measured throughout a 44-h midweek interdialytic period. Pre-dialysis ABI was evaluated with a BOSO ABI device. An ABI value <0.9 or ≥1.3 was defined as abnormal. RESULTS: In the whole study group (72 % males, mean age 67 ± 14 years), there was an increase in BP (p < 0.05) and in systolic BP night/day ratio (n/dSR, p = 0.01) during the interdialytic period. Patients with abnormal ABI (n = 29) more frequently had a positive history for cerebrovascular accident and PAD and higher proBNP values than those with normal ABI (n = 52). No difference was detected among ABPM-derived components except for the n/dSR (p = 0.02). Patients with abnormal ABI showed a significantly increased n/dSR (p = 0.02) and ambulatory arterial stiffness index (AASI) (p = 0.006) on the second day compared to the first. Patients with n/dSR >1 during day 2 (n = 34) were older, showed significantly higher proBNP and AASI and were more likely to reveal abnormal ABI compared to those with a lower n/dSR (p = 0.006). CONCLUSIONS: Abnormal ABI in HD patients is associated to changes in interdialytic ABPM pattern, namely higher n/dSR on day 2. These data may indicate the pathophysiological mechanisms underlying the worse outcome observed in HD patients.