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.

Long-term blood pressure behavior and progression to end-stage renal disease in patients with immunoglobulin A nephropathy: a single-center observational study in Italy.

BACKGROUND: Antihypertensive treatment by the use of RAAS inhibitors (RAAS-is) is of paramount importance in the management of slowly progressive IgA nephropathy (IgAN). With the aim of better understanding the relationship between BP behavior and progression, we looked at time-averaged SBP and time-averaged proteinuria and renal outcome in a single-center cohort of IgAN patients. METHODS: Among 248 consecutive patients referred to the Clinic of Nephrology of San Martino Hospital from 1996 to 2018 for native renal biopsy with a diagnosis of IgAN, we retrospectively analyzed 145 with available data at baseline and during follow-up. All patients received Supportive Care, 39% were on RAAS-is alone, 45% plus steroids, and 16% plus steroids and immunosuppressors. Renal replacing treatment (RRT) was the primary endpoint. RESULTS: During a mean follow-up of 67 ±â€Š6 months, 23% of study patients (n = 33) progressed to RRT and 6% (n = 9) died. Patients who reached the renal endpoint, had lower baseline eGFR and higher proteinuria and proteinuria indexed at baseline. Moreover, they had higher TA-SBP (139 ±â€Š17 vs. 130 ±â€Š13, P = 0.0016). The incidence of RRT was higher in IgAN patients in the highest time-averaged SBP tertile as compared with the others (32 vs. 23 vs. 9%, χ 6.8, P = 0.033). After adjusting for baseline SBP, baseline and time-averaged proteinuria indexed, MEST-C score, and treatment, the association between TA-SBP and RRT persisted. CONCLUSION: Time-averaged low BP values were independently associated to a decreased risk of renal progression in IgAN with no evidence of a J-curve relationship even at SBP levels below 125 mmHg.

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.

Long-term blood pressure variability and development of chronic kidney disease in type 2 diabetes.

OBJECTIVE: Long-term visit-to-visit SBP variability (VVV) has been shown to predict cerebro-cardiovascular events and end-stage renal disease in chronic kidney disease (CKD) patients. Whether SBP VVV is also a predictor of CKD development in diabetes is currently uncertain. We assessed the role of SBP VVV on the development of CKD in patients with type 2 diabetes (T2D) and hypertension in real life. METHODS: Clinical records from 30 851 patients with T2D and hypertension, with normal estimated glomerular filtration rate (eGFR) and regular visits during a 4-year follow-up were analyzed. SBP variability was measured by three metrics: coefficient of variation; SD of the mean SBP and average absolute difference of successive values in each individual. CKD was defined as eGFR less than 60 and/or a reduction in eGFR at least 30% from baseline. RESULTS: Over the 4-year follow-up, 9.7% developed eGFR less than 60 and 4.5% an eGFR reduction at least 30% from baseline. Several clinical characteristics (older age, male sex, SBP, DBP, albuminuria, glycated hemoglobin, insulin treatment) were related to intraindividual SBP variability. Patients with VVV in the upper quintile showed an increased risk of developing both components of CKD [adjusted odds ratio (OR) 1.21, P < 0.001 and 1.32, P < 0.001, respectively]. The multivariable adjusted ORs of SBP coefficient of variation quintiles 2-5 for the incidence of CKD were incrementally higher (OR 1.04, P = 0.601, OR 1.05, P = 0.520, OR 1.21, P < 0.017 and OR 1.42, P < 0.001 as compared with the first quintile). CONCLUSION: Increased long-term BP variability predicts CKD in patients with T2D and hypertension.

Endothelin-1/nitric oxide balance and HOMA index in children with excess weight and hypertension: a pathophysiological model of hypertension.

The aim of this study was to investigate the relationship between endothelin-1, nitric oxide, insulin resistance, and blood pressure in young subjects with a high prevalence of excess weight and/or elevated blood pressure. In a cohort of 238 children (mean age = 11.1 years), height, weight, waist circumference, and blood pressure were assessed. Body mass index, waist-to-height ratio, and blood pressure percentiles were calculated, and the children were classified as having excess weight and elevated blood pressure according to the International Obesity Task Force and the US blood pressure nomograms specific for gender, age and height, respectively. Endothelin-1 and nitric oxide production were assessed, and the homeostatic model assessment index was calculated. Forty-three percent of children were male, 71% had excess weight, and 37% had systolic and/or diastolic values above the ninetieth percentile. Plasma endothelin-1 and nitric oxide production were independently correlated (p < 0.05). In multivariate analyses, the HOMA index was associated with systolic and diastolic blood pressure (p = 0.01), and nitric oxide was independently related to diastolic blood pressure (p = 0.04), even after adjustment for measures of body composition. By using the waist-to-height ratio instead of BMI in the statistical model, the association between the homeostatic model assessment index and blood pressure was attenuated, while the results remained similar for nitric oxide. No correlation was found between endothelin-1 and blood pressure. In our study population, the correlation between nitric oxide and blood pressure and the lack of a relationship between endothelin-1 and blood pressure could be explained by an increase in the vasodilator effect of local and systemic nitric oxide, which counteracts the possible hypertensive effect of endothelin-1.

Uric acid and angiotensin II additively promote inflammation and oxidative stress in human proximal tubule cells by activation of toll-like receptor 4.

Renal proximal tubular cells (PTECs) participate in several mechanisms of innate immunity, express toll-like receptors (TLRs), and proinflammatory cytokines. Hyperuricemia may be a promoter of inflammation and renal damage. Angiotensin II (Ang II) modulate immune and inflammatory responses in renal tubular cells. With the aim to evaluate the effect of uric acid (UA) and Ang II on oxidative stress and inflammation mediated by toll-like receptor 4 (TLR4) activation in human PTECs, human kidney 2 (HK2) were incubated for 24 hr with UA (12 mg/dl) and Ang II (10 -7 M). HK2 were pretreated with an antagonist of TLR4 (TAK 242), valsartan or losartan. The genic expression of TLR4, monocyte chemoattractant protein-1 (MCP1), and Nox4 was quantified with reverse transcription polymerase chain reaction, proteins were evaluated with Western blot. The incubation of HK2 either with UA or with Ang II determines an increased expression of TLR4, production of proinflammatory cytokines as MCP1 and pro-oxidants as Nox4 ( p < 0.05). TAK 242 attenuates the expression of MCP1 induced both by UA and Ang II. Valsartan attenuated all the effects we described after exposure to Ang II but not those observed after UA exposure. At variance, pretreatment with losartan, which inhibits UA internalization, attenuates the expression of TLR4, MCP1, and Nox4 in cells previously treated with UA, Ang II, and UA plus Ang II. Proinflammatory pathways are induced in an additive manner by UA and Ang II ( p < 0.05) and might be mediated by TLR4 in PTECs. Renin-angiotensin-aldosterone system (RAAS) activation, hyperuricemia, and innate immunity interplay in the development of chronic tubular damage and the interaction of several nephrotoxic mechanisms blunt the protective effect of RAAS inhibition.

[mTOR inhibitors in kidney transplantation].

A changing paradigm of treatment of kidney transplant recipients is a new, wider approach to immunosuppression, which should take into account both antiviral and anticancer effects, in addition to cardiovascular protection. Recent observations suggest that the early introduction of mammalian target of rapamycin inhibitors (mTORi) in association with low dose CNI may offer many of these effects. The present manuscript summarizes benefits and contraindications of combinations with mTORi in kidney transplant immunosuppressive strategies.

Hypertensive Versus HIV-infected Patients: Who Has the Greatest Target Organ Damage? Comparison of Carotid Plaque Prevalence, Intima Media Thickness and Renal Resistive Index in the Two Groups of Patients.

OBJECTIVES: to compare the prevalence of target-organ damage (TOD), defined as carotid plaque, or intima media thickness, cIMT, >0.9 mm, and that of increased renal resistive index (RRI), among HIV-1-infected patients and uninfected hypertensive patients (HT-non HIV). METHODS: HIV-infected patients aged ≥ 18 years and virologically suppressed were matched with pair-age, sex and BMI HT-non HIV. Patients on antihypertensive treatment were excluded. All patients' cIMT and RRI were evaluated with ultrasonography. Data were analysed throughout Χ2 test, analysis of variance and logistic regression. RESULTS: Fifty-nine HIV-infected patients were enrolled (71% men) and matched with 59 HT-non HIV. No differences were found in cIMT values (p=0.827) and in the prevalence of TOD between HIV-infected patients and HT-non HIV (36% vs 38%, p= 0.79). Among HIV-infected patients, those hypertensive had significantly higher prevalence of TOD (46% vs 21%, P< 0.05) and higher cIMT (0.747 ± 0.104 vs 0.654 ±0.100 mm, p = 0.0185). Patients with TOD were older (p= 0.004) and more frequently current smokers (p= 0.022). At the logistic regression analysis, TOD was significantly related to age (p=0.04, 95%CI 1.0-1.1) and smoke, current (p=0.178, 95%CI1.2-12.8) or previous (p=0.04, 95%CI 1.0-7.2). Mean RRI were identical for both HIV-1 infected and uninfected patients (0.60, SD± 0.05 and 0.60, SD± 0.04, respectively, p=0.996). CONCLUSIONS: In our study TOD was associated to hypertension, older age and smoke, but not to HIV serostatus itself, confirming the major importance of traditional risk factors and the need of risk assessment and cardiovascular prevention measures in HIV-infected patients.

[The uric acid cardio-nephropathy].

Uric acid is a product of purine catabolism formed by the activity of xanthine-oxidase and prevalently excreted by the kidney. In vivo, urate is known to have both an anti- or pro-oxidant role depending on several biological conditions. New evidence suggests that chronic hyperuricemia can contribute to hypertension development, kidney disease and cardiovascular risk. The pathophysiologic mechanisms are various, such as endothelial dysfunction and oxidative stress, vasoconstriction and stimulation of renin angiotensin system. These processes act at the kidney level, within arterioles and tubular cells, as well as at the systemic vasculature and tissue level causing hypertension, atherosclerosis and myocardial dysfunction. In recent years evidence has grown that asymptomatic hyperuricemia is a possible risk factor for the development of hypertension, diabetes as well as renal and cardiovascular events. Preliminary clinical evidence suggests that lowering uric acid levels by the use of xanthine-oxidase inhibitors may improve cardiovascular and renal risk. Several ongoing trials, both with allopurinol and febuxostat, will clarify this issue in the upcoming years.

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.

Changes in albuminuria and cardiovascular risk under antihypertensive treatment: a systematic review and meta-regression analysis.

BACKGROUND: Increased urine albumin excretion (UAE) is a well known predictor of cardiovascular events in patients with primary hypertension. Whether a reduction in UAE is associated to an improvement in cardiovascular risk is at present unclear. We performed a systematic review and meta-regression analysis of available trials to investigate whether treatment-induced changes in UAE are related to cardiovascular outcome. METHODS: We searched MEDLINE, ISIWeb of Science, Cochrane Database and Scopus for studies including hypertensive patients, which reported cardiovascular events and UAE at baseline and at end of follow-up. RESULTS: In trials reporting pairwise comparisons between antihypertensive treatment for cardiovascular outcome (16 randomized controlled trials and 48 580 patients, mean follow-up 45 months, 5867 cardiovascular events) after adjustment for differences in achieved blood pressure, a relationship between changes in albuminuria and risk was evident in the presence of a relevant between-arms difference in albuminuria [relative risks (RR) pooled 0.45, confidence interval (CI) 0.23-0.85] but not when no improvement in UAE was found between randomized arms (RR pooled 1.04, 95% CI 0.86-1.26, P for difference between subgroups <0.001). Meta-regression analysis showed a relationship between changes in albuminuria and risk after adjustment for blood pressure variation under treatment (adj. coeff. 0.005, 95% CI 0.0005-0.0096, P = 0.033, R 34.8%). In studies reporting changes in cardiovascular events on the basis of UAE variations (six trials and 36 325 patients, mean follow-up 60 months, 3741 cardiovascular events), the overall adjusted RR of total cardiovascular events was 0.51 (95% CI 0.38-0.59, P = 0.000) for albuminuria regression/stable vs increase. CONCLUSION: Reduction in UAE under antihypertensive treatment is associated with reduced risk of clinical cardiovascular events. Our findings suggest that UAE changes may represent a valuable intermediate end point for cardiovascular events in primary hypertension.

Renin-angiotensin-aldosterone system blockade in chronic kidney disease: current strategies and a look ahead.

The Renin-Angiotensin-Aldosterone System (RAAS) is profoundly involved in the pathogenesis of renal and cardiovascular organ damage, and has been the preferred therapeutic target for renal protection for over 30 years. Monotherapy with either an Angiotensin Converting Enzime Inhibitor (ACE-I) or an Angiotensin Receptor Blocker (ARB), together with optimal blood pressure control, remains the mainstay treatment for retarding the progression toward end-stage renal disease. Combining ACE-Is and ARBs, or either one with an Aldosterone Receptor Antagonist (ARA), has been shown to provide greater albuminuria reduction, and to possibly improve renal outcome, but at an increased risk of potentially severe side effects. Moreover, combination therapy has failed to provide additional cardiovascular protection, and large prospective trials on hard renal endpoints are lacking. Therefore this treatment should, at present, be limited to selected patients with residual proteinuria and high renal risk. Future studies with novel agents, which directly act on the RAAS at multiple levels or have a more favourable side effect profile, are greatly needed to further explore and define the potential for and the limitations of profound pharmacologic RAAS inhibition.

[Hyperuricemia and renal risk]. / Iperuricemia e rischio renale.

Recent studies have revealed an association between elevated levels of uric acid and conditions correlated to chronic kidney diseases such as hypertension, cardiovascular and cerebral disease, insulin resistance. Several pathogenetic mechanisms at cellular and tissue levels could justify a direct correlation between serum uric acid levels and renal damage. Growing evidence indicating a correlation between urate lowering therapy and renal morbidity could encourage the use of urate lowering therapy in primary or secondary prevention in chronic kidney disease.

[Hyperuricemia, diabetes and hypertension]. / Iperuricemia, diabete, ipertensione: un'associazione casuale?

Hyperuricemia is frequently found in association with several condition predisposing to cardiovascular events such as arterial hypertension and diabetes mellitus. This has led researchers to investigate possible pathogenetic mechanisms underlying this association. Several experimental studies and some indirect clinical evidence support a causal link between mild hyperuricemia and the developement of hypertension as well as new onset diabetes. At the tissue level, chronic exposure to increased uric acid has been shown to promote vascular changes leading to renal ischemia as well as stimulation of the renin angiotensin system. Furthermore, uric acid has been shown to promote the development of insulin resistance, hypertrglyceridemia and haepatic steatosis through pro-oxidative mechanisms. These experimental pathophysiological changes may be partly preventable by hypouricemic treatments. Whether clinical implications of these findings are confirmed by solid clinical intervention trials, mild hyperuricemia may soon change its status from risk predictor to treatment target for patients at high cardiovascular and renal risk.