Molecular Targets of Novel Therapeutics for Diabetic Kidney Disease: A New Era of Nephroprotection.

Diabetic kidney disease (DKD) is a chronic microvascular complication in patients with diabetes mellitus (DM) and the leading cause of end-stage kidney disease (ESKD). Although glomerulosclerosis, tubular injury and interstitial fibrosis are typical damages of DKD, the interplay of different processes (metabolic factors, oxidative stress, inflammatory pathway, fibrotic signaling, and hemodynamic mechanisms) appears to drive the onset and progression of DKD. A growing understanding of the pathogenetic mechanisms, and the development of new therapeutics, is opening the way for a new era of nephroprotection based on precision-medicine approaches. This review summarizes the therapeutic options linked to specific molecular mechanisms of DKD, including renin-angiotensin-aldosterone system blockers, SGLT2 inhibitors, mineralocorticoid receptor antagonists, glucagon-like peptide-1 receptor agonists, endothelin receptor antagonists, and aldosterone synthase inhibitors. In a new era of nephroprotection, these drugs, as pillars of personalized medicine, can improve renal outcomes and enhance the quality of life for individuals with DKD.

Left ventricular remodeling response to SGLT2 inhibitors in heart failure: an updated meta-analysis of randomized controlled studies.

BACKGROUND: Randomized controlled trials (RCTs) reported contrasting results about reverse left ventricular remodeling (LVR) after sodium-glucose co-transporter-2 inhibitors (SGLT2i) therapy in patients with heart failure (HF). METHODS AND RESULTS: We performed a metanalysis of RCTs of SGLT2i administration in HF outpatients published until June 2022 searching four electronic databases. The protocol has been published in PROSPERO. Primary LVR outcome was change in absolute LV end-diastolic (LVEDV) and end-systolic volume (LVESV) from baseline to study endpoint. Secondary outcomes included changes in LVEDV and LVESV indexed to body surface area, LV Mass index (LVMi), LV ejection fraction (LVEF), and N-terminal pro-B-type natriuretic peptide (NTproBNP). Mean differences (MDs) with 95% CIs were pooled. A total of 9 RCTs (1385 patients) were analyzed. All of them reported data on LVEF. Six trials reported data on LVESV and LVEDV (n = 951); LVMi was available in 640. SGLT2i treatment significantly reduced LVEDV [MD= -10.59 ml (-17.27; -3.91), P = 0.0019], LVESV [MD= -8.80 ml (-16.91; -0.694), P = 0.0334], and LVMI [MD= -5.34 gr/m2 (-9.76; -0.922), P = 0.0178], while LVEF significantly increased [MD = + 1.98% (0.67; 0.306), P = 0.0031]. By subgroup analysis, the beneficial effects of SGLT2i on LVEF did not differ by imaging method used, time to follow-up re-evaluation, or HF phenotype. Reduction in LV volumes tended to be greater in HF with reduced EF (HFrEF) than in those with preserved EF (HFpEF), while the opposite was observed for LVMi. CONCLUSIONS: Treatment with SGLT2i significantly reversed cardiac volumes, improving LV systolic function and LV mass, particularly in HFrEF patients.

Hyperuricemia increases the risk of cardiovascular mortality associated with very high HdL-cholesterol level.

BACKGROUND AND AIMS: Whether the association between very high HDL-cholesterol levels and cardiovascular mortality (CVM) is modulated by some facilitating factors is unclear. Aim of the study was to investigate whether the risk of CVM associated with very high HDL-cholesterol is increased in subjects with hyperuricemia. METHODS AND RESULTS: Multivariable Cox analyses were made in 18,072 participants from the multicentre URRAH study stratified by sex and HDL-cholesterol category. During a median follow-up of 11.4 years there were 1307 cases of CVM. In multivariable Cox models a J-shaped association was found in the whole population, with the highest risk being present in the high HDL-cholesterol group [>80 mg/dL, adjusted hazard ratio (HR), 1.28; 95%CI, 1.02-1.61; p = 0.031)]. However, a sex-specific analysis revealed that this association was present only in women (HR, 1.34; 95%CI, 1.02-1.77; p = 0.034) but not in men. The risk of CVM related to high HDL-cholesterol was much greater in the women with high uric acid (>0.30 mmol/L, HR 1.61; 95%CI, 1.08-2.39) than in those with low uric acid (HR, 1.17; 95%CI, 0.80-1.72, p for interaction = 0.016). In women older than 70 years with hyperuricemia the risk related to high HDL-cholesterol was 1.83 (95%CI, 1.19-2.80, p < 0.005). Inclusion of BMI in the models weakened the strength of the associations. CONCLUSION: Our data indicate that very high HDL-cholesterol levels in women are associated with CVM in a J-shaped fashion. The risk of CVM is increased by concomitant hyperuricemia suggesting that a proinflammatory/oxidative state can enhance the detrimental cardiovascular effects associated with high HDL-cholesterol.

Serum uric acid levels threshold for mortality in diabetic individuals: The URic acid Right for heArt Health (URRAH) project.

BACKGROUND AND AIM: The URRAH (URic acid Right for heArt Health) Study has identified cut-off values of serum uric acid (SUA) predictive of total mortality at 4.7 mg/dl, and cardiovascular (CV) mortality at 5.6 mg/dl. Our aim was to validate these SUA thresholds in people with diabetes. METHODS AND RESULTS: The URRAH subpopulation of people with diabetes was studied. All-cause and CV deaths were evaluated at the end of follow-up. A total of 2570 diabetic subjects were studied. During a median follow-up of 107 months, 744 deaths occurred. In the multivariate Cox regression analyses adjusted for several confounders, subjects with SUA ≥5.6 mg/dl had higher risk of total (HR: 1.23, 95%CI: 1.04-1.47) and CV mortality (HR:1.31, 95%CI:1.03-1.66), than those with SUA <5.6 mg/dl. Increased all-cause mortality risk was shown in participants with SUA ≥4.7 mg/dl vs SUA below 4.7 mg/dl, but not statistically significant after adjustment for all confounders. CONCLUSIONS: SUA thresholds previously proposed by the URRAH study group are predictive of total and CV mortality also in people with diabetes. The threshold of 5.6 mg/dl can predict both total and CV mortality, and so is candidate to be a clinical cut-off for the definition of hyperuricemia in patients with diabetes.

Lessons Learnt during the COVID-19 Pandemic: For Patients with End-Stage Renal Disease, We Should Prioritize Home-Based Treatment and Telemedicine.

BACKGROUNDS: The recent coronavirus disease 2019 (CO-VID-19) pandemic has placed worldwide health systems and hospitals under pressure, and so are the renal care models. This may be a unique opportunity to promote and expand alternative models of health-care delivery in patients undergoing renal replacement therapies. SUMMARY: Despite the high risk of acquiring communicable diseases when undergoing in-centre treatments, only a small proportion of patients are currently being treated with home therapies. Recent data provided by the Italian Society of Nephrology (SIN), the REIN French Registry and the Wuhan Hemodialysis Quality Control Center clearly show that patients receiving hospital-based treatment have a 3- to 4-fold greater risk of infection, and a subsequent fatality proportion between 21 and 34%. On the other hand, home-based therapy can be managed remotely, there is little or no need for transport to and from the hospital, and it is less expensive. Besides, the digital revolution in health care with the development of virtual care systems can make home dialysis with telehealth a cost-effective solution for both patients and health-care providers. Such a transition would require specific training for physicians and health-care professionals and a functional re-organization of dialysis centres to improve the skills and expertise in caring for patients at home. CONCLUSION: The need for more widespread home treatment is the main lesson learnt by nephrologists by the COVID-19 pandemic.

Hypertension and Atrial Fibrillation: Doubts and Certainties From Basic and Clinical Studies.

Hypertension and atrial fibrillation (AF) are 2 important public health priorities. Their prevalence is increasing worldwide, and the 2 conditions often coexist in the same patient. Hypertension and AF are strikingly related to an excess risk of cardiovascular disease and death. Hypertension ultimately increases the risk of AF, and because of its high prevalence in the population, it accounts for more cases of AF than other risk factors. Among patients with established AF, hypertension is present in about 60% to 80% of individuals. Despite the well-known association between hypertension and AF, several pathogenetic mechanisms underlying the higher risk of AF in hypertensive patients are still incompletely known. From an epidemiological standpoint, it is unclear whether the increasing risk of AF with blood pressure (BP) is linear or threshold. It is uncertain whether an intensive control of BP or the use of specific antihypertensive drugs, such as those inhibiting the renin-angiotensin-aldosterone system, reduces the risk of subsequent AF in hypertensive patients in sinus rhythm. Finally, in spite of the observational evidence suggesting a progressive relation between BP levels and the risk of thromboembolism and bleeding in patients with hypertension and AF, the extent to which BP should be lowered in these patients, including those who undergo catheter ablation, remains uncertain. This article summarizes the main basic mechanisms through which hypertension is believed to promote AF. It also explores epidemiological data supporting an evolutionary pathway from hypertension to AF, including the emerging evidence favoring an intensive BP control or the use of drugs, which inhibit the renin-angiotensin-aldosterone system to reduce the risk of AF. Finally, it examines the impact of non-vitamin K antagonist oral anticoagulants compared with warfarin in relation to hypertension.

Indications for renal biopsy in patients with diabetes. Joint position statement of the Italian Society of Nephrology and the Italian Diabetes Society.

AIMS: This joint document of the Italian Society of Nephrology and the Italian Diabetes Society reviews the main indications to perform a renal biopsy in diabetic patients, according to the recommendations of a panel of experts based on all available scientific evidence. DATA SYNTHESIS: Renal biopsy has a pivotal role in assessing the nature and severity of renal injury in patients with diabetic kidney disease (DKD). The procedure is mandatory in the presence of one of more of the following features: rapid onset or progression of albuminuria or sudden onset of nephrotic syndrome, rapid GFR decline with or without albuminuria, hematuria, active urine sediment, clinical and/or laboratory suspicion of other systemic diseases, and, in patients with type 1 diabetes, short diabetes duration and absence of retinopathy. Indeed, ~40% of diabetic individuals with kidney injury undergoing renal biopsy are affected by a non-diabetic renal disease (NDRD). Furthermore, the histological evaluation of patients with suspected classical diabetic nephropathy allows to define the extent of glomerular, tubulo-interstitial and vascular lesions, thus providing important prognostic (and potentially therapeutic) data. In the future, the indications for renal biopsy might be extended to the definition of the histological lesions underlying the "nonalbuminuric" DKD phenotypes, as well as to the evaluation of the response to treatment with the new anti-hyperglycemic drugs that provide cardiorenal protection. CONCLUSIONS: In view of the heterogeneous clinical presentation and course of DKD and of the related heterogeneous histopathological patterns, a more extensive use of renal biopsy may be crucial to provide valuable information with important pathogenic, diagnostic, prognostic, and therapeutic implications.

The revolution of the anti-diabetic drugs in cardiology.

Beginning in December 2008, under the auspices of Food and Drug Administration, numerous controlled clinical trial were planned, and in part completed, concerning the cardiovascular (CV) effects of hypoglycaemic drug in patients with Type 2 diabetes mellitus. At least 9 studies have been concluded, 13 are still open, and 4 have been initiated and closed ahead of time. Of the nine completed studies, three concerned inhibitor of the dipeptidyl peptidase 4 (inhibitors of DPP-4), four the glucagon-like peptide 1 agonist (GLP-1 agonist), and two the inhibitor of sodium-glucose co-transporter-2 (inhibitors of SGLT-2). Only four studies demonstrated the superiority, and not the mere 'non-inferiority', of the anti-diabetic drugs compared to placebo, in addition to standard treatment, in terms of reduction of the primary endpoint (CV death, non-fatal myocardial infarction, and non-fatal stroke). Two of the four studies regarded GLP-1 analogues (liraglutide and semaglutide), and two inhibitors of SGLT-2 (empaglifozin and canaglifozin). As a whole, these studies provided solid data supporting major beneficial CV effects of anti-diabetic drugs. During the next 3-4 years, an equal number of studies will be completed and published, so we will soon have the 'final word' on this issue. In the meantime, the clinical cardiologist should become familiar with these drugs, selecting the patients able to gain the best clinical advantage from this treatment, also by establishing a close relationship with the diabetologist.

Diabetic kidney disease: New clinical and therapeutic issues. Joint position statement of the Italian Diabetes Society and the Italian Society of Nephrology on "The natural history of diabetic kidney disease and treatment of hyperglycemia in patients with type 2 diabetes and impaired renal function".

AIMS: This joint document of the Italian Diabetes Society and the Italian Society of Nephrology reviews the natural history of diabetic kidney disease (DKD) in the light of the recent epidemiological literature and provides updated recommendations on anti-hyperglycemic treatment with non-insulin agents. DATA SYNTHESIS: Recent epidemiological studies have disclosed a wide heterogeneity of DKD. In addition to the classical albuminuric phenotype, two new albuminuria-independent phenotypes have emerged, i.e., "nonalbuminuric renal impairment" and "progressive renal decline", suggesting that DKD progression toward end-stage kidney disease (ESKD) may occur through two distinct pathways, albuminuric and nonalbuminuric. Several biomarkers have been associated with decline of estimated glomerular filtration rate (eGFR) independent of albuminuria and other clinical variables, thus possibly improving ESKD prediction. However, the pathogenesis and anatomical correlates of these phenotypes are still unclear. Also the management of hyperglycemia in patients with type 2 diabetes and impaired renal function has profoundly changed during the last two decades. New anti-hyperglycemic drugs, which do not cause hypoglycemia and weight gain and, in some cases, seem to provide cardiorenal protection, have become available for treatment of these individuals. In addition, the lowest eGFR safety thresholds for some of the old agents, particularly metformin and insulin secretagogues, have been reconsidered. CONCLUSIONS: The heterogeneity in the clinical presentation and course of DKD has important implications for the diagnosis, prognosis, and possibly treatment of this complication. The therapeutic options for patients with type 2 diabetes and impaired renal function have substantially increased, thus allowing a better management of these individuals.

Detrimental Impact of Chronic Obstructive Pulmonary Disease in Atrial Fibrillation: New Insights from Umbria Atrial Fibrillation Registry.

Background and objectives: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Among extra-pulmonary manifestations of COPD, atrial fibrillation (AF) is commonly observed in clinical practice. The coexistence of COPD and AF significantly affects the risk of cardiovascular morbidity and mortality. Nonetheless, the mechanisms explaining the increased risk of vascular events and death associated to the presence of COPD in AF are complex and not completely understood. We analyzed data from an Italian network database to identify markers and mediators of increased vascular risk among subjects with AF and COPD. Materials and Methods: Cross-sectional analysis of the Umbria Atrial Fibrillation (Umbria-FA) Registry, a multicenter, observational, prospective on-going registry of patients with non-valvular AF. Of the 2205 patients actually recruited, 2159 had complete clinical data and were included in the analysis. Results: the proportion of patients with COPD was 15.6%. COPD patients had a larger proportion of permanent AF when compared to the control group (49.1% vs. 34.6%, p < 0.0001) and were more likely to be obese and current smokers. Other cardiovascular risk factors including chronic kidney disease (CKD), peripheral artery disease and subclinical atherosclerosis were more prevalent in COPD patients (all p < 0.0001). COPD was also significantly associated with higher prevalence of previous vascular events and a history of anemia (all p < 0.0001). The thromboembolic and bleeding risk, as reflected by the CHA2DS2VASc and HAS-BLED scores, were higher in patients with COPD. Patients with COPD were also more likely to have left ventricular (LV) hypertrophy at standard ECG than individuals forming the cohort without COPD (p = 0.018). Conclusions: AF patients with COPD have a higher risk of vascular complications than AF patients without this lung disease. Our analysis identified markers and mediators of increased risk that can be easily measured in clinical practice, including LV hypertrophy, CKD, anemia, and atherosclerosis of large arteries.

Glomerular hyperfiltration is a predictor of adverse cardiovascular outcomes.

The association between glomerular hyperfiltration and cardiovascular events is not well known. To investigate whether glomerular hyperfiltration is independently associated with risk of adverse outcome we analyzed 8794 participants, average age 52 years enrolled in 8 prospective studies. Of these, 89% had hypertension. Using the 5th and 95th percentiles of the age- and sex-specific quintiles of CKD-EPI-calculated estimated glomerular filtration rate (eGFR), we identified three participant groups with low, high and normal eGFR. The ambulatory pulse pressure interval was wider and nighttime blood pressure fall was smaller in both the low and high than in the normal eGFR participants. During a mean follow-up of 6.2 years, there were 722 cardiovascular events. Crude event rates were significantly higher for both high (1.8 per 100-person-year) and low eGFR groups (2.1 per 100 person-year) as compared with group with normal eGFR (1.2 per 100 person-year). In multivariable Cox models including age, sex, average 24-hour blood pressure, smoking, diabetes, and cholesterol, both high eGFR (hazard ratio 1.5 (95% confidence interval 1.2-2.1) and low eGFR (2.0 [1.5-2.6]) participants had a significantly higher risk of cardiovascular events as compared to those with normal eGFR. Addition of body mass index to the multivariable survival model did not change the magnitude of hazard estimates. Thus, glomerular hyperfiltration is a strong and independent predictor of cardiovascular events in a large multiethnic population of predominantly hypertensive individuals. Our findings support a U-shaped relationship between eGFR and adverse outcome.

Dabigatran vs. warfarin in relation to the presence of left ventricular hypertrophy in patients with atrial fibrillation- the Randomized Evaluation of Long-term anticoagulation therapY (RE-LY) study.

Aim: We tested the hypothesis that left ventricular hypertrophy (LVH) interferes with the antithrombotic effects of dabigatran and warfarin in patients with atrial fibrillation (AF). Methods and results: This is a post-hoc analysis of the Randomized Evaluation of Long-term anticoagulation therapY (RE-LY) Study. We defined LVH by electrocardiography (ECG) and included patients with AF on the ECG tracing at entry. Hazard ratios (HR) for each dabigatran dose vs. warfarin were calculated in relation to LVH. LVH was present in 2353 (22.7%) out of 10 372 patients. In patients without LVH, the rates of primary outcome were 1.59%/year with warfarin, 1.60% with dabigatran 110 mg (HR vs. warfarin 1.01, 95% confidence interval (CI) 0.75-1.36) and 1.08% with dabigatran 150 mg (HR vs. warfarin 0.68, 95% CI 0.49-0.95). In patients with LVH, the rates of primary outcome were 3.21%/year with warfarin, 1.69% with dabigatran 110 mg (HR vs. warfarin 0.52, 95% CI 0.32-0.84) and 1.55% with 150 mg (HR vs. warfarin 0.48, 95% CI 0.29-0.78). The interaction between LVH status and dabigatran 110 mg vs. warfarin was significant for the primary outcome (P = 0.021) and stroke (P = 0.016). LVH was associated with a higher event rate with warfarin, not with dabigatran. In the warfarin group, the time in therapeutic range was significantly lower in the presence than in the absence of LVH. Conclusions: LVH was associated with a lower antithrombotic efficacy of warfarin, but not of dabigatran, in patients with AF. Consequently, the relative benefit of the lower dose of dabigatran compared to warfarin was enhanced in patients with LVH. The higher dose of dabigatran was superior to warfarin regardless of LVH status. Clinical trial registration: http:www.clinicaltrials.gov. Unique identifier: NCT00262600.

The lowest well tolerated blood pressure: A personalized target for all?

The optimal blood pressure (BP) target for prevention of cardiovascular complications of hypertension remains uncertain. Most Guidelines suggest different targets depending on age, comorbidities and treatment tolerability, but the underlying evidence is not strong. Results of randomized strategy trials comparing lower (i.e., more intensive) versus higher (i.e., less intensive) BP targets should drive the definition. However, these trials tested different BP targets based on systolic BP, diastolic BP or combined systolic and diastolic BP goals. Overall, the more intensive treatment targets reduced the risk of major cardiovascular complications of hypertension when compared with the less intensive targets, despite a higher incidence of unwanted effects including, but not limited to, hypotension, electrolyte abnormalities and renal dysfunction. Consequently, some Guidelines defined low BP thresholds (i.e., 120/70 mmHg) not to exceed downward because of the expectation that unwanted effects may outweigh the outcome benefits. The present review discusses the evidence underlying the choice of BP targets, which remains an important step in the management of hypertensive patients. We conclude that, on the ground of the heterogeneity of available data in support to fixed BP targets, their definition should be personalized in all patients and based on best trade-off between efficacy and safety, i.e., the lowest well tolerated BP.

Prognostic impact of hypertension grading.

BACKGROUND: Most Hypertension Guidelines grade hypertension according to various cut-off values. We sought to investigate the prognostic impact of Grades 1 (140-159 and/or 90-99 mmHg), 2 (160-179 and/or 100-109 mmHg) and 3 (≥180 and/or ≥110 mmHg). METHODS: We followed for an average of 10 years a cohort of 3,150 initially untreated hypertensive patients (mean age 50 years, 44 % women) with no previous cardiovascular disease at entry. All patients underwent diagnostic tests including 24-hour ambulatory blood pressure (BP) monitoring. RESULTS: At entry, average clinic BP was 156/97 mmHg and average 24-hour BP was 137/87 mmHg. During follow-up, 314 patients experienced a first major cardiovascular event (composite of non-fatal myocardial infarction or stroke, cardiovascular death, or hospitalization for heart failure). Event rate was not formally dissimilar between Grade 1 and Grade 2 (0.73 vs 0.95 per 100 patient-years, respectively; p = 0.06). It was higher in Grade 3 (1.93 per 100 patient-years; p < 0.01 vs Grade 1 and Grade 2). After adjustment for a robust set of covariables, the hazard ratio was not dissimilar between Grade 1 and Grade 2 (p = 0.27), and higher in Grade 3 than in Grade 1 (p < 0.01), but the excess risk in Grade 3 was no longer significant (hazard ratio: 1.25, 95 % CI 0.87-1.78; p = 0.22) after adjustment for 24-hour ambulatory systolic BP. CONCLUSIONS: We were unable to find a significant difference in the relative hazard of cardiovascular events tied to hypertension Grades 1 and 2. Conversely, Grade 3 (clinic BP ≥180/110 mmHg) portends a higher cardiovascular risk, which is associated with higher levels of 24-hour ambulatory BP.