Poor Adherence to the Mediterranean Diet and Sleep Disturbances Are Associated with Migraine Chronification and Disability among an Adult Population in the Lazio Region, Italy.

Lifestyle factors, such as diet and sleep quality, are receiving increasing interest as accessible therapeutic approaches to migraine. The Mediterranean diet (MD) has shown clear benefits in cardiovascular and metabolic diseases, as well as in sleep patterns. Here, our objective was to identify the impact of adherence to the MD and other lifestyle factors on the clinical burden of migraine. For this purpose, we enrolled 170 migraine patients and 100 controls, assessing the clinical disability of headache using standardized clinical scales (HIT-6 and MIDAS) in the migraineur cohort and lifestyle patterns in both groups through the PREDIMED score for MD adherence, the IPAQ scale for physical activity, and BMI. Subjects were also screened for sleep-wake disturbances based on the Pittsburgh Sleep Quality Index (PSQI). We found that migraine patients had lower adherence to the MD compared to the controls and that the HIT-6 scale had a significant negative relationship with MD adherence in patients with high-frequency episodic and chronic migraine. Additionally, in the same migraine patients, the presence of sleep-wake disturbances was correlated with greater migraine disability as assessed by the MIDAS score. In conclusion, this study found that among different lifestyle factors, poor adherence to the MD and the presence of sleep-wake disturbances were closely associated with migraine disability and chronification.

Innovative Treatments to Counteract Endothelial Dysfunction in Chronic Kidney Disease Patients.

In chronic kidney disease (CKD) patients, several risk factors contribute to the development of endothelial dysfunction (ED), which can be described as an alteration in the cell structure or in the function of the endothelium. Among the well-known CKD-related risk factors capable of altering the production of endothelium-derived relaxing factors, we include asymmetric dimethylarginine increase, reduced dimethylarginine dimethylamine hydrolase enzyme activity, low-grade chronic systemic inflammation, hyperhomocysteinemia, oxidative stress, insulin resistance, alteration of calcium phosphorus metabolism, and early aging. In this review, we also examined the most important techniques useful for studying ED in humans, which are divided into indirect and direct methods. The direct study of coronary endothelial function is considered the gold standard technique to evaluate if ED is present. In addition to the discussion of the main pharmacological treatments useful to counteract ED in CKD patients (namely sodium-glucose cotransporter 2 inhibitors and mineralocorticoid receptor antagonist), we elucidate innovative non-pharmacological treatments that are successful in accompanying the pharmacological ones. Among them, the most important are the consumption of extra virgin olive oil with high intake of minor polar compounds, adherence to a plant-dominant, low-protein diet (LPD), an adaptive physical activity program and, finally, ketoanalogue administration in combination with the LPD or the very low-protein diet.

Potential Anti-Inflammatory and Anti-Fatigue Effects of an Oral Food Supplement in Long COVID Patients.

Long coronavirus disease (COVID) syndrome leads to chronic inflammatory state onset that can have a multisystem impact and compromise organ function. Moreover, long COVID syndrome is often characterized by the presence of chronic fatigue, which affects subjects' daily activities and worsens their quality of life. The aim of our double-blind, placebo-controlled randomized trial (protocol code RS 150.21, approved on 4 November 2021) was to evaluate the beneficial effects of the consumption of 2 cps/day, for two months, of an oral food supplement (OFS), based on Echinacea angustifolia, rosehip, propolis, royal jelly and zinc, in long COVID patients, compared to a two-month placebo period. The OFS's vitamin C content was equal to 22.17 mg/g (8.87 mg/capsule). The OFS's total polyphenol content was 43.98 mg/g gallic acid equivalents. At the end of the in vivo study, we highlighted a significant decrease in the inflammatory parameters in the OFS period, compared to the placebo period (neutrophil-to-lymphocyte ratio, p = 0.0455; monocyte to-lymphocyte ratio, p = 0.0005; C-reactive protein, p = 0.0145). Our study also highlighted a significant increase in vitamin D serum values (p = 0.0005) and, at the same time, an improvement in patients' life quality and a reduction in fatigue, monitored by the fatigue severity scale. This study showed the OFS's beneficial effects on the inflammatory state, fatigue and quality of life in long COVID patients.

Linking Migraine to Gut Dysbiosis and Chronic Non-Communicable Diseases.

In the world, migraine is one of the most common causes of disability in adults. To date, there is no a single cause for this disorder, but rather a set of physio-pathogenic triggers in combination with a genetic predisposition. Among the factors related to migraine onset, a crucial role seems to be played by gut dysbiosis. In fact, it has been demonstrated how the intestine is able to modulate the central nervous system activities, through the gut-brain axis, and how gut dysbiosis can influence neurological pathologies, including migraine attacks. In this context, in addition to conventional pharmacological treatments for migraine, attention has been paid to an adjuvant therapeutic strategy based on different nutritional approaches and lifestyle changes able to positively modulate the gut microbiota composition. In fact, the restoration of the balance between the different gut bacterial species, the reconstruction of the gut barrier integrity, and the control of the release of gut-derived inflammatory neuropeptides, obtained through specific nutritional patterns and lifestyle changes, represent a possible beneficial additive therapy for many migraine subtypes. Herein, this review explores the bi-directional correlation between migraine and the main chronic non-communicable diseases, such as diabetes mellitus, arterial hypertension, obesity, cancer, and chronic kidney diseases, whose link is represented by gut dysbiosis.

Saliva as Biomarker for Oral and Chronic Degenerative Non-Communicable Diseases.

Saliva is a very complex fluid and it is essential to maintain several physiological processes and functions, including oral health, taste, digestion and immunological defenses. Saliva composition and the oral microbiome can be influenced by several factors, like diet and smoking habits, and their alteration can represent an important access point for pathogens and, thus, for systemic illness onset. In this review, we explore the potentiality of saliva as a new tool for the early detection of some pathological conditions, such as oral diseases, chronic degenerative non-communicable diseases, among these chronic kidney disease (CKD). We also examined the possible correlation between oral and systemic diseases and oral and gut microbiota dysbiosis. In particular, we deeply analyzed the relationship between oral diseases and CKD. In this context, some salivary parameters can represent a new device to detect either oral or systemic pathologies. Moreover, the positive modulation of oral and gut microbiota induced by prebiotics, postbiotics, or symbiotics could represent a new possible adjuvant therapy in the clinical management of oral diseases and CKD.

The Onco-Nephrology Field: The Role of Personalized Chemotherapy to Prevent Kidney Damage.

In recent years, the onco-nephrology field has acquired a relevant role in internal medicine due to the growing number of cases of renal dysfunction that have been observed in cancer patients. This clinical complication can be induced by the tumor itself (for example, due to obstructive phenomena affecting the excretory tract or by neoplastic dissemination) or by chemotherapy, as it is potentially nephrotoxic. Kidney damage can manifest as acute kidney injury or represent a worsening of pre-existing chronic kidney disease. In cancer patients, physicians should try to set preventive strategies to safeguard the renal function, avoiding the concomitant use of nephrotoxic drugs, personalizing the dose of chemotherapy according to the glomerular filtration rate (GFR) and using an appropriate hydration therapy in combination with nephroprotective compounds. To prevent renal dysfunction, a new possible tool useful in the field of onco-nephrology would be the development of a personalized algorithm for the patient based on body composition parameters, gender, nutritional status, GFR and genetic polymorphisms.

Possible Beneficial Effects of Hydrolyzable Tannins Deriving from Castanea sativa L. in Internal Medicine.

Hydrolyzable tannins (HTs) deriving from chestnuts have demonstrated, through numerous studies, the ability to exert multiple beneficial effects, including antioxidant and antimicrobial effects, on the lipid metabolism and cancer cells. The latter effect is very fascinating, since different polyphenols deriving from chestnuts were able to synergistically induce the inhibition of cancerous cells through multiple pathways. Moreover, the main mechanisms by which tannins induce antioxidant functions include: the reduction in oxidative stress, the ability to scavenge free radicals, and the modulation of specific enzymes, such as superoxide dismutase. HTs have also been shown to exert significant antimicrobial activity by suppressing microbial growth. The actions on the lipid metabolism are several, among which is the inhibition of lipid accumulation. Thus, tannins seem to induce a cardioprotective effect. In fact, through various mechanisms, such as the relaxation of the vascular smooth muscle, HTs were proven to be efficient against arterial hypertension. Therefore, the great number of studies in this field prove the growing interest on the utilization of natural bioactive compounds, such as HTs deriving from natural sources or obtained by circular economy models, as potential nutraceuticals or adjuvants therapies.

Extra Virgin Olive Oil and Cardiovascular Protection in Chronic Kidney Disease.

The high mortality related to chronic kidney disease (CKD) is not only due to the disease itself; in fact, CKD also represents an important risk factor for cardiovascular (CV) morbidity and mortality. Among the functional foods that seems to have cardioprotective action, extra virgin olive oil (EVOO) plays a pivotal health-promoting role. The aim of this study was to evaluate the possible cardioprotective effects of an EVOO containing a very high content (>900 ppm) of minor phenolic compounds (MPCs). The selected EVOO was analyzed by HPLC-DAD-MS to establish the MPC content. The Olea extract obtained from the selected EVOO was tested against the RAW 264.7 cell line in order to investigate its anti-inflammatory activity. We enrolled 40 CKD patients under conservative therapy for in vivo clinical testing. All CKD patients consumed 40 mL/day of raw EVOO for 9 weeks (T1). At baseline (T0) and at T1, we monitored the patients' blood and urinary parameters. The patients' body composition was assessed using bioelectrical impedance analysis and the carotid intima-media thickness (CIMT) using ultrasound imaging. At T1, we observed a decrease in inflammatory parameters, CIMT, and oxidative stress biomarkers. We also noticed improvements in lipid and purine metabolism, atherogenic indices, and body composition. Thus, this study highlighted the cardioprotective action of EVOO in nephropathic patients.

The Impact of Chronic Kidney Disease on Nutritional Status and Its Possible Relation with Oral Diseases.

Several studies have demonstrated a strong relation between periodontal diseases and chronic kidney disease (CKD). The main mechanisms at the base of this link are malnutrition, vitamin dysregulation, especially of B-group vitamins and of C and D vitamins, oxidative stress, metabolic acidosis and low-grade inflammation. In particular, in hemodialysis (HD) adult patients, an impairment of nutritional status has been observed, induced not only by the HD procedures themselves, but also due to numerous CKD-related comorbidities. The alteration of nutritional assessment induces systemic manifestations that have repercussions on oral health, like oral microbiota dysbiosis, slow healing of wounds related to hypovitaminosis C, and an alteration of the supporting bone structures of the oral cavity related to metabolic acidosis and vitamin D deficiency. Low-grade inflammation has been observed to characterize periodontal diseases locally and, in a systemic manner, CKD contributes to the amplification of the pathological process, bidirectionally. Therefore, CKD and oral disease patients should be managed by a multidisciplinary professional team that can evaluate the possible co-presence of these two pathological conditions, that negatively influence each other, and set up therapeutic strategies to treat them. Once these patients have been identified, they should be included in a follow-up program, characterized by periodic checks in order to manage these pathological conditions.

The Impact of Functional Bars and Adapted Physical Activity on Quality of Life in Chronic Kidney Disease: A Pilot Study.

Chronic kidney disease (CKD) represents a public health problem because it is characterized by several comorbidities, including uremic sarcopenia (US), and a poor quality of life. Currently, there are no standardized treatments available to counteract the onset of US but only some possible therapeutic approaches to slow its progression. The aim of this pilot study is to collect descriptive data in order to design a clinical trial based on the power analysis and simple size. The purpose of this pilot study was to evaluate the possible beneficial action induced by the functional anti-inflammatory and antioxidant bars in combination with the adapted physical activity (APA), on the onset and progression of US and other related-CKD comorbidities. We enrolled 21 CKD patients under conservative therapy, divided into four groups: (A) the physical exercise program (PEP), three times a week, in combination with the daily consumption of the two functional bars group; (B) the PEP group; (C) the daily consumption of the two functional bars group; (D) the control group. The duration of the study protocol was 12 weeks. We observed an improvement trend of body composition, blood pressure levels, lipid metabolism, and functional test in A and B groups. These preliminary data would seem to confirm the effectiveness of APA and to demonstrate the additive role of the natural bioactive compound's assumption in countering US and other CKD comorbidities.

Effect of Online Home-Based Training on Functional Capacity and Strength in Two CKD Patients: A Case Study.

Chronic kidney disease (CKD) is a clinical condition characterized by the loss of kidney function over time, as well as several complications affecting gastrointestinal, cardiovascular, and musculoskeletal systems. Physical exercise seems to induce positive adaptations in CKD patients, without side effects. Usually, these patients show a reduced physical activity and physical performance. The aim of this case-report was to evaluate the effects of an online training protocol on functional capacity and on muscle mass, in CKD stage III patients. Methods: Two CKD (stage III according to KDIGO guidelines) participants (1 female, Patient A; 1 male, Patient B) were enrolled and they performed an online tailored-supervised combined training lasting 12 weeks, including multi-joint strength exercises using TheraBand and an aerobic session at 65-70% of the patients' heart rate reserve. Results: Both patients showed an improving trend on functional capacity (6 min walking test: Patient A = +3%; Patient B = +5.3%) and on strength of the upper arms (handgrip strength test-right: Patient A = +13.4%; Patient B = +19.1%; handgrip strength test-left: Patient A = +42.8%; Patient B= +12.9%), as well as a reduction in inflammation and oxidative stress biomarkers. The protocol was feasible, and no side effects were evidenced. These case studies suggest that the online combined training can produce beneficial effects in CKD patients under conservative therapy, by reducing the CKD-related complications and improving the adherence to exercise of this population of patients, overcoming logistic barriers such as transportation, availability of facilities, and working and personal-life schedule.

Effects of Ultramicronized Palmitoylethanolamide (um-PEA) in COVID-19 Early Stages: A Case-Control Study.

Ultramicronized palmitoylethanolamide (um-PEA), a compound with antioxidant, anti-inflammatory and neuroprotective properties, appears to be a potential adjuvant treatment for early stages of Coronavirus disease 2019 (COVID-19). In our study, we enrolled 90 patients with confirmed diagnosis of COVID-19 that were randomized into two groups, homogeneous for age, gender and BMI. The first group received oral supplementation based on um-PEA at a dose of 1800 mg/day for a total of 28 days; the second group was the control group (R.S. 73.20). At baseline (T0) and after 28 days of um-PEA treatment (T1), we monitored: routine laboratory parameters, inflammatory and oxidative stress (OS) biomarkers, lymphocytes subpopulation and COVID-19 serological response. At T1, the um-PEA-treated group presented a significant reduction in inflammation compared to the control group (CRP p = 0.007; IL-6 p = 0.0001; neutrophils to lymphocytes ratio p = 0.044). At T1, the controls showed a significant increase in OS compared to the treated group (FORT p = 0.05). At T1, the um-PEA group exhibited a significant decrease in D-dimer levels (p = 0.0001) and higher levels of IgG against SARS-CoV-2 (p = 0.0001) compared to the controls. Our data demonstrated, in a randomized clinical trial, the beneficial effects of um-PEA in both asymptomatic and mild-symptomatic patients related to reductions in inflammatory state, OS and coagulative cascade alterations.

Natural Bioactive Compounds in the Management of Oral Diseases in Nephropathic Patients.

Among the chronic non-communicable degenerative diseases (CDNCDs), chronic kidney disease (CKD) represents a global public health problem. Recent studies demonstrate a mutual cause-effect relationship between CKD and oral diseases, in which the presence of one induces the onset and faster progression of the other. In particular, the oral cavity alterations more frequent in CKD patients are: chronic periodontitis diseases, bone lesions, oral infections, and oral cancer lesions. Currently, a standardized therapy for the treatment of oral diseases is lacking. For this reason, natural bioactive compounds (NBCs), characterized by several health effects, such as antioxidant, antimicrobial, anti-inflammatory and anti-cancer actions, represent a new possible adjuvant therapy in the management of these pathological conditions. Among NBCs, polyphenols play a leading role due to positive modulation of oral microbiota, preventing and correcting oral dysbiosis. Moreover, these compounds exert anti-inflammatory effects, such as inhibiting the production of pro-inflammatory cytokines and the expression of cycloxigenase-2. In this light, the formulation of a new mouthwash/gel/gingival paste, with a high content of polyphenols in association with NBCs characterized by antimicrobial action, could represent a future therapy of oral disease in CKD patients.

Nutritional Approaches for the Management of Metabolic Acidosis in Chronic Kidney Disease.

Metabolic acidosis is a severe complication of chronic kidney disease (CKD) which is associated with nefarious impairments such as bone demineralization, muscle wasting, and hormonal alterations, for example, insulin resistance. Whilst it is possible to control this condition with alkali treatment, consisting in the oral administration of sodium citrate or sodium bicarbonate, this type of intervention is not free from side effects. On the contrary, opting for the implementation of a targeted dietetic-nutritional treatment for the control of CKD metabolic acidosis also comes with a range of additional benefits such as lipid profile control, increased vitamins, and antioxidants intake. In our review, we evaluated the main dietary-nutritional regimens useful to counteract metabolic acidosis, such as the Mediterranean diet, the alkaline diet, the low-protein diet, and the vegan low-protein diet, analyzing the potentialities and limits of every dietary-nutritional treatment. Literature data suggest that the Mediterranean and alkaline diets represent a valid nutritional approach in the prevention and correction of metabolic acidosis in CKD early stages, while the low-protein diet and the vegan low-protein diet are more effective in CKD advanced stages. In conclusion, we propose that tailored nutritional approaches should represent a valid therapeutic alternative to counteract metabolic acidosis.

Impact of Physical Activity and Natural Bioactive Compounds on Endothelial Dysfunction in Chronic Kidney Disease.

Chronic kidney disease (CKD) represents a world-wide public health problem. Inflammation, endothelial dysfunction (ED) and vascular calcifications are clinical features of CKD patients that increase cardiovascular (CV) mortality. CKD-related CV disease pathogenic mechanisms are not only associated with traditional factors such as arterial hypertension and dyslipidemia, but also with ED, oxidative stress and low-grade inflammation. The typical comorbidities of CKD contribute to reduce the performance and the levels of the physical activity in nephropathic patients compared to healthy subjects. Currently, the effective role of physical activity on ED is still debated, but the available few literature data suggest its positive contribution. Another possible adjuvant treatment of ED in CKD patients is represented by natural bioactive compounds (NBCs). Among these, minor polar compounds of extra virgin olive oil (hydroxytyrosol, tyrosol and oleocanthal), polyphenols, and vitamin D seem to exert a beneficial role on ED in CKD patients. The objective of the review is to evaluate the effectiveness of physical exercise protocols and/or NBCs on ED in CKD patients.

Gut Dysbiosis and Western Diet in the Pathogenesis of Essential Arterial Hypertension: A Narrative Review.

Metabolic syndrome is a cluster of the most dangerous cardiovascular (CV) risk factors including visceral obesity, insulin resistance, hyperglycemia, alterations in lipid metabolism and arterial hypertension (AH). In particular, AH plays a key role in the complications associated with metabolic syndrome. High salt intake is a well-known risk factor for AH and CV diseases. Vasoconstriction, impaired vasodilation, extracellular volume expansion, inflammation, and an increased sympathetic nervous system (SNS) activity are the mechanisms involved in the pathogenesis of AH, induced by Western diet. Gut dysbiosis in AH is associated with reduction of short chain fatty acid-producing bacteria: acetate, butyrate and propionate, which activate different pathways, causing vasoconstriction, impaired vasodilation, salt and water retention and a consequent high blood pressure. Moreover, increased trimethylamine N-oxide and lipopolysaccharides trigger chronic inflammation, which contributes to endothelial dysfunction and target organs damage. Additionally, a high salt-intake diet impacts negatively on gut microbiota composition. A bidirectional neuronal pathway determines the "brain-gut" axis, which, in turn, influences blood pressure levels. Then, we discuss the possible adjuvant novel treatments related to gut microbiota modulation for AH control.

Ultramicronized Palmitoylethanolamide (um-PEA): A New Possible Adjuvant Treatment in COVID-19 patients.

The Coronavirus Disease-19 (COVID-19) pandemic has caused more than 100,000,000 cases of coronavirus infection in the world in just a year, of which there were 2 million deaths. Its clinical picture is characterized by pulmonary involvement that culminates, in the most severe cases, in acute respiratory distress syndrome (ARDS). However, COVID-19 affects other organs and systems, including cardiovascular, urinary, gastrointestinal, and nervous systems. Currently, unique-drug therapy is not supported by international guidelines. In this context, it is important to resort to adjuvant therapies in combination with traditional pharmacological treatments. Among natural bioactive compounds, palmitoylethanolamide (PEA) seems to have potentially beneficial effects. In fact, the Food and Drug Administration (FDA) authorized an ongoing clinical trial with ultramicronized (um)-PEA as an add-on therapy in the treatment of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection. In support of this hypothesis, in vitro and in vivo studies have highlighted the immunomodulatory, anti-inflammatory, neuroprotective and pain-relieving effects of PEA, especially in its um form. The purpose of this review is to highlight the potential use of um-PEA as an adjuvant treatment in SARS-CoV-2 infection.

Natural Bioactive Compounds Useful in Clinical Management of Metabolic Syndrome.

Metabolic syndrome (MetS) is a clinical manifestation characterized by a plethora of comorbidities, including hyperglycemia, abdominal obesity, arterial hypertension, and dyslipidemia. All MetS comorbidities participate to induce a low-grade inflammation state and oxidative stress, typical of this syndrome. MetS is related to an increased risk of cardiovascular diseases and early death, with an important impact on health-care costs. For its clinic management a poly-pharmaceutical therapy is often required, but this can cause side effects and reduce the patient's compliance. For this reason, finding a valid and alternative therapeutic strategy, natural and free of side effects, could represent a useful tool in the fight the MetS. In this context, the use of functional foods, and the assumption of natural bioactive compounds (NBCs), could exert beneficial effects on body weight, blood pressure and glucose metabolism control, on endothelial damage, on the improvement of lipid profile, on the inflammatory state, and on oxidative stress. This review focuses on the possible beneficial role of NBCs in the prevention and in the clinical management of MetS and its comorbidities.

Effect of Hydrolysable Tannins and Anthocyanins on Recurrent Urinary Tract Infections in Nephropathic Patients: Preliminary Data.

Urinary tract infections (UTIs) are caused by uropathogenic microorganism colonization. UTIs often require an antibiotic therapy that can cause the selection of antibiotic-resistant bacterial strains. A natural bioactive compound may represent a valid therapeutic adjuvant approach, in combination with drug therapy. In this paper, we present a pilot study, based on the administration of an oral food supplement (OFS), containing chestnut tannins and anthocyanins, to nephropathic patients suffering from recurrent UTIs (16 treated patients with 1 cp/day and 10 untreated patients). We performed laboratory tests and quality of life and body composition assessments, at T0 (baseline) and T1 (after 6 weeks OFS assumption). The analysis of OFS was performed by HPLC-DAD-MS for its content in polyphenols and by in vitro tests for its antioxidative and anti-free radical activities. In each capsule, polyphenol content was 6.21 mg (4.57 mg hydrolysable tannins, 0.94 mg anthocyanosides, 0.51 mg proanthocyanidins, 0.18 mg quercetin derivatives). A significant reduction of erythrocyte sedimentation rate was observed only in male patients. Urinalysis showed a significant reduction of leukocytes in both genders, whereas urinary bacterial flora at T1 significantly decreased only in male subjects. Tannins seem to exert an antimicrobial action according to gender, useful to counteract the recurrence of UTIs.

Usefulness of Extra Virgin Olive Oil Minor Polar Compounds in the Management of Chronic Kidney Disease Patients.

Chronic kidney disease (CKD) is one of the most common chronic non-communicable degenerative diseases and it represents an important risk factor for cardiovascular morbidity and mortality. The Mediterranean diet, in which extra virgin olive oil (EVOO) is the main source of vegetal fats, represents a nutritional-diet regimen that is useful for the treatment of CKD and its comorbidities. We tested two different EVOOs, characterized by a high (Synergy) and medium (Luxolio) content of minor polar compounds (MPCs), detected by HPLC-DAD-MS analysis, in 40 nephropathic patients, at a dose of 40 mL/day for 9 weeks. We evaluated the effects of these two EVOOs on renal function, body composition, oxidative stress, and inflammatory state, after 9 weeks of EVOOs consumption (T1) and after 2 months of wash-out (T2). We observed an improvement of renal function biomarkers (estimated-glomerular filtration rate, albuminuria, azotemia, uric acid), lipid profile, oxidative stress, inflammatory parameters (erythrocyte sedimentation rate, C-reactive protein) and in body composition at T1. These healthy effects were greater and persisted over time after the wash-out period in Synergy patients. The high MPC EVOO content seems to exert an antioxidant and anti-inflammatory effect in nephropathic patients and these protective actions are maintained over time.