Obesity and chronic kidney disease (CKD) are public health priorities that share core pathophysiological mechanisms. However, whether high body mass index (BMI) increases risk of CKD de novo remains ill-defined. To evaluate the role of BMI in predicting CKD onset in the general adult population, we performed a systematic review and meta-analysis of PubMed and ISI Web of Science databases articles published between January 2000 and August 2016 without language restriction. We selected studies in adult individuals from a general population with normal renal function at baseline that reported the risk of low estimated glomerular filtration (eGFR) (under 60 mL/min/1.73m) and/or albuminuria (1+ at dipstick or an albumin creatinine ratio of 3.4 mg/mmol or more) as hazard ratio, odds ratio or relative risk related to obesity, overweight, or BMI as continuous value. A total of 39 cohorts covering 630, 677 participants with a mean follow-up of 6.8 years were selected. Obesity increased the relative risk, 95% confidence interval and heterogeneity (I) of developing low eGFR (1.28, 1.07-1.54, [I: 95.0%]) and albuminuria (1.51, 1.36-1.67, [I: 62.7%]). Increase of BMI unit was also associated with higher risk of low eGFR (1.02, 1.01-1.03, [I: 24.3%]) and albuminuria (1.02, 1.00-1.04, [I: 0%]). Conversely, overweight did not predict onset of either low eGFR (1.06, 0.94-1.21, [I: 50.0%]) or albuminuria (1.24, 0.98-1.58, [I: 49.4%]). Thus, a high BMI predicts onset of albuminuria without kidney failure (CKD stages 1-2) as well as CKD stages 3 and higher, the effect being significant only in obese individuals. Hence, our findings may have implications to improve risk stratification and recommendations on body weight control in the general population.

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We provide evidence that patients with non-proteinuric DM-CKD are not exposed to higher cardiorenal risk. In contrast, in the presence of moderate proteinuria and diabetes per se is associated with a higher risk of mortality and CV events, whereas the entity of abnormal proteinuria modulates ESRD risk independent of diabetes.

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Background. A clear evidence on the benefits of reducing salt in people with chronic kidney disease (CKD) is still lacking. Salt restriction in CKD may allow better control of blood pressure (BP) as shown in a previous systematic review while the effect on proteinuria reduction remains poorly investigated. Methods. We performed a meta-analysis of randomized controlled trials (RCTs) evaluating the effects of low versus high salt intake in adult patients with non-dialysis CKD on change in BP, proteinuria and albuminuria. Results. Eleven RCTs were selected and included information about 738 CKD patients (Stage 1–4); urinary sodium excretion was 104 mEq/day (95%CI, 76–131) and 179 mEq/day (95%CI, 165–193) in low- and high-sodium intake subgroups, respectively, with a mean difference of −80 mEq/day (95%CI from −107 to −53; p <0.001). Overall, mean differences in clinic and ambulatory systolic BP were −4.9 mmHg (95%CI from −6.8 to −3.1, p <0.001) and −5.9 mmHg (95%CI from −9.5 to −2.3, p <0.001), respectively, while clinic and ambulatory diastolic BP were −2.3 mmHg (95%CI from −3.5 to −1.2, p <0.001) and −3.0 mmHg (95%CI from −4.3 to −1.7; p <0.001), respectively. Mean differences in proteinuria and albuminuria were −0.39 g/day (95%CI from −0.55 to −0.22, p <0.001) and −0.05 g/day (95%CI from −0.09 to −0.01, p = 0.013). Conclusion. Moderate salt restriction significantly reduces BP and proteinuria/albuminuria in patients with CKD (Stage 1–4).

Chronic kidney disease (CKD), defined by an estimated glomerular filtration rate <60 ml/min/1.73 m 2 and/or an increase in urine protein excretion (i.e., albuminuria), is an important public health problem. Prevalence and incidence of CKD have risen by 87 and 89%, worldwide, over the last three decades. The onset of either albuminuria and eGFR reduction has found to predict higher cardiovascular (CV) risk, being this association strong, independent from traditional CV risk factors and reproducible across different setting of patients. Indeed, this relationship is present not only in high risk cohorts of CKD patients under regular nephrology care and in those with hypertension or type 2 diabetes, but also in general, otherwise healthy population. As underlying mechanisms of damage, it has hypothesized and partially proved that eGFR reduction and albuminuria can directly promote endothelial dysfunction, accelerate atherosclerosis and the deleterious effects of hypertension. Moreover, the predictive accuracy of risk prediction models was consistently improved when eGFR and albuminuria have been added to the traditional CV risk factors (i.e., Framingham risk score). These important findings led to consider CKD as an equivalent CV risk. Although it is hard to accept this definition in absence of additional reports from scientific Literature, a great effort has been done to reduce the CV risk in CKD patients. A large number of clinical trials have tested the effect of drugs on CV risk reduction. The targets used in these trials were different, including blood pressure, lipids, albuminuria, inflammation, and glucose. All these trials have determined an overall better control of CV risk, performed by clinicians. However, a non-negligible residual risk is still present and has been attributed to: (1) missed response to study treatment in a consistent portion of patients, (2) role of many CV risk factors in CKD patients not yet completely investigated. These combined observations provide a strong argument that kidney measures should be regularly included in individual prediction models for improving CV risk stratification. Further studies are needed to identify high risk patients and novel therapeutic targets to improve CV protection in CKD patients.

Chronic Kidney Disease (CKD) represents a risk factor for fatal and nonfatal cardiovascular (CV) events, including peripheral vascular disease (PVD). This occurs because CKD encompasses several factors that lead to poor prognoses, mainly due to a reduction of the estimated glomerular filtration rate (eGFR), the presence of proteinuria, and the uremic inflammatory milieu. The matrix metalloproteinases (MMPs) are a group of zinc-containing endopeptidases implicated in extracellular matrix (ECM) remodeling, a systemic process in tissue homeostasis. MMPs play an important role in cell differentiation, angiogenesis, inflammation, and vascular damage. Our aim was to review the published evidence regarding the association between MMPs, PVD, and CKD to find possible common pathophysiological mechanisms. MMPs favor ECM deposition through the glomeruli, and start the shedding of cellular junctions and epithelial-mesenchymal transition in the renal tubules. MMP-2 and -9 have also been associated with the presence of systemic vascular damage, since they exert a pro-inflammatory and proatherosclerotic actions. An imbalance of MMPs was found in the context of PVD, where MMPs are predictors of poor prognoses in patients who underwent lower extremity revascularization. MMP circulating levels are increased in both conditions, i.e., that of CKD and PVD. A possible pathogenic link between these conditions is represented by the enhanced production of transforming growth factor-β that worsens vascular calcifications and atherosclerosis and the development of proteinuria in patients with increased levels of MMPs. Proteinuria has been recognized as a marker of systemic vascular damage, and this may explain in part the increase in CV risk that is manifest in patients with CKD and PVD. In conclusion, MMPs can be considered a useful tool by which to stratify CV risk in patients with CKD and PVD. Further studies are needed to investigate the causal-relationships between MMPs, CKD, and PVD, and to optimize their prognostic and predictive (in response to treatments) roles.

Background: SGLT2 inhibitors and MRAs reduce the urinary albumin-to-creatinine ratio (UACR) and confer kidney and cardiovascular protection in patients with chronic kidney disease (CKD). We assessed efficacy and safety of the SGLT2 inhibitor dapagliflozin and mineralocorticoid receptor antagonists (MRA) eplerenone alone and in combination in patients with CKD. Methods: We conducted a randomized open-label cross-over trial in patients with urinary albumin excretion ≥100 mg/24-hour, eGFR 30-90 mL/min/1.73m2, who had been receiving maximum tolerated stable doses of an ACE inhibitor (ACEi) or angiotensin receptor blocker (ARB). Patients were assigned to 4-week treatment periods with dapagliflozin 10 mg/day, eplerenone 50 mg/day, or their combination in random order, separated by 4-week wash-out periods. Primary outcome was the correlation in UACR changes between treatments. Secondary outcome was the percent change in 24-hour UACR from baseline. Results: Of 57 patients screened, 46 were randomly assigned (mean eGFR 58.1 mL/min/1.73m2, median UACR 401 mg/g) to the three groups. Mean percentage change from baseline in UACR after 4 weeks treatment with dapagliflozin, eplerenone, and dapagliflozineplerenone was -19.6% (95%CI -34.3, -1.5), -33.7% (95%CI -46.1, -18.5), and -53.0% (95%CI -61.7, -42.4; p<0.001 vs dapagliflozin; p=0.0127 vs eplerenone). UACR change during dapagliflozin or eplerenone treatment did not correlate with UACR change during dapagliflozineplerenone (r=-0.13; p=0.473; r=-0.08; p=0.658 respectively). Hyperkalemia was more frequently reported with eplerenone (N=8, [17.4%]) compared to dapagliflozin (N=0, [0%]) or dapagliflozin-eplerenone (N=2, [4.3%]; Pbetween-groups=0.0033). Conclusion: Albuminuria changes in response to dapagliflozin and eplerenone did not correlate, supporting systematic rotation of these therapies to optimize treatment. Combining dapagliflozin with eplerenone resulted in a robust additive UACR lowering effect. A larger trial in this population is required to confirm long-term efficacy and safety of combined SGLT2 inhibitor and MRA treatment.