Natural History and Clinicopathological Associations of TRPC6-Associated Podocytopathy.

BACKGROUND: Understanding the genetic basis of human diseases has become integral to drug development and precision medicine. Recent advancements have enabled the identification of molecular pathways driving diseases, leading to targeted treatment strategies. The increasing investment in rare diseases by the biotech industry underscores the importance of genetic evidence in drug discovery and approval processes. Here we studied a monogenic Mendelian kidney disease, TRPC6-associated podocytopathy (TRPC6-AP), to present its natural history, genetic spectrum, and clinicopathological associations in a large cohort of patients with causal variants in TRPC6, in order to help define the specific features of disease and further facilitate drug development and clinical trials design. METHODS: the study involved 64 individuals from 39 families with TRPC6 causal missense variants. Clinical data, including age of onset, laboratory results, response to treatment, kidney biopsy findings, and genetic information, were collected from multiple centers nationally and internationally. Exome or targeted sequencing was performed and variant classification was based on strict criteria. Structural and functional analyses of TRPC6 variants were conducted to understand their impact on protein function. In depth re-analysis of light and electron microscopy specimens for 9 available kidney biopsies was conducted to identify pathological features and correlates of TRPC6-AP. RESULTS: Large-scale sequencing data did not support causality for TRPC6 protein-truncating variants. We identified 21 unique TRPC6 missense variants, clustering in three distinct regions of the protein, and with different effects on TRPC6 3D protein structure. Kidney biopsy analysis revealed FSGS patterns of injury in most cases, along with distinctive podocyte features including diffuse foot process effacement and swollen cell bodies. The majority of patients presented in adolescence or early adulthood but with ample variation (average 22, SD ± 14 years), with frequent progression to kidney failure but with variability in time between presentation and ESKD. CONCLUSIONS: This study provides insights into the genetic spectrum, clinicopathological associations, and natural history of TRPC6-AP.

Sex-dependent effects of antimicrobials and lipopolysaccharide on blood-brain-barrier permeability in pubertal male and female CD1 mice.

Exposure to stressors during puberty can disrupt normal development and possibly increase susceptibility to neurodegenerative disorders later in life. However, the mechanisms underlying the relationship between pubertal stress exposure and neurodegeneration remain unclear. As such, the current study was designed to examine the effects of pubertal antimicrobial (AMNS) and lipopolysaccharide (LPS) treatments on intestinal and blood-brain-barrier (BBB) permeability in male and female mice. Moreover, we also examined the sex-specific effects of pubertal AMNS and LPS treatments on gross motor activity, heart rate, and core body temperature. At four weeks of age, male and female CD1 mice were implanted with the G2 HR E-Mitter telemetry system. At five weeks of age, mice received 200 µL of broad-spectrum antimicrobial or water, through oral gavage, twice daily for seven days. Mice received an intraperitoneal injection of either saline or LPS at six weeks of age. BBB and intestinal permeability were examined 24 h, 72 h, and one week post-LPS/saline treatment. Telemetric data was collected for 48 h post-LPS/saline treatment. The results showed that pubertal AMNS and LPS treatments increased sickness behaviours and decreased body temperature and heart rate, in a sex-dependent manner. Furthermore, pubertal AMNS and LPS treatments resulted in sex-dependent regional increases in BBB permeability 24 h and 72 h post-LPS/saline treatment, while global increases in BBB permeability were only observed one week post-LPS/saline treatment. These results further our understanding of the combined effects of AMNS and LPS treatments on physiology and on the enduring negative changes observed following pubertal exposure to stressors.

Pathophysiology of Physical Exercise in Kidney Patients: Unveiling New Players - The Role of Myokines.

BACKGROUND: Chronic kidney disease (CKD) is a progressive systemic condition characterized by numerous complications. Among these, alterations in skeletal muscle physiology, such as sarcopenia, are particularly significant, as they are associated with poor outcomes and reduced quality of life. SUMMARY: Various interventions, including pharmacological approaches and lifestyle modifications have been investigated to slow CKD progression and prevent or treat its complications. Physical exercise, in particular, has emerged as a promising intervention with multiple beneficial effects. These include improvements in physical functioning, increased muscle mass, modulation of metabolic abnormalities, and reduced cardiovascular risk. However, the pathophysiology of physical exercise in patients with kidney disease is complex and remains only partially understood. A crucial advancement in understanding this phenomenon has been the identification of myokines - molecules expressed and released by skeletal muscle in response to physical activity. These myokines can exert both paracrine and systemic effects, influencing not only skeletal muscle physiology but also other processes such as energy metabolism and lipid regulation. KEY MESSAGES: The interplay among skeletal muscle, physical activity, and myokines may act as a pivotal regulator in various physiological processes, including aging, as well as in pathological conditions like cachexia and sarcopenia, frequently observed in CKD patients at different stages, including patients on dialysis. Despite the potential importance of this relationship, only a limited number of studies have explored the relationship between exercise and myokine, and the effect of this interaction on experimental models or individuals with kidney disease. In the following sections, we review and discuss this topic.

How Do Physical Activity and Exercise Affect Fabry Disease? Exploring a New Opportunity.

BACKGROUND: Fabry disease (FD) is a multisystem, monogenic, X-linked storage disorder caused by mutations in the GLA gene, resulting in reduced alfa-galactosidase A enzyme activity. This effect leads to the accumulation of glycosphingolipids, particularly globotriaosylceramide, in various tissues, including the heart, kidney, vasculature, smooth muscle, and peripheral nervous system. Hemizygous males are usually more severely affected than females, in whom random inactivation of an X chromosome may lead to variable phenotype. SUMMARY: Among the manifestations of FD, exercise intolerance is commonly diagnosed but often underestimated, even though it significantly limits quality of life, especially in young patients. This review primarily discusses the various pathophysiological mechanisms involved in exercise intolerance in FD patients, such as altered muscle composition, compromised cardiopulmonary framework, and peripheral neuropathy. Secondarily, it explores the potential effect of available therapy, including enzyme replacement therapy and chaperone therapy (migalastat), in reducing exercise intolerance while considering the potential impact of physical activity and exercise training as adjunctive treatments. CONCLUSION: Exercise intolerance has a major impact on the well-being of people with FD. Exercise training can play an important role in addition to drug therapy.

Rare Single Nucleotide and Copy Number Variants and the Etiology of Congenital Obstructive Uropathy: Implications for Genetic Diagnosis.

SIGNIFICANCE STATEMENT: Congenital obstructive uropathy (COU) is a prevalent human developmental defect with highly heterogeneous clinical presentations and outcomes. Genetics may refine diagnosis, prognosis, and treatment, but the genomic architecture of COU is largely unknown. Comprehensive genomic screening study of 733 cases with three distinct COU subphenotypes revealed disease etiology in 10.0% of them. We detected no significant differences in the overall diagnostic yield among COU subphenotypes, with characteristic variable expressivity of several mutant genes. Our findings therefore may legitimize a genetic first diagnostic approach for COU, especially when burdening clinical and imaging characterization is not complete or available. BACKGROUND: Congenital obstructive uropathy (COU) is a common cause of developmental defects of the urinary tract, with heterogeneous clinical presentation and outcome. Genetic analysis has the potential to elucidate the underlying diagnosis and help risk stratification. METHODS: We performed a comprehensive genomic screen of 733 independent COU cases, which consisted of individuals with ureteropelvic junction obstruction ( n =321), ureterovesical junction obstruction/congenital megaureter ( n =178), and COU not otherwise specified (COU-NOS; n =234). RESULTS: We identified pathogenic single nucleotide variants (SNVs) in 53 (7.2%) cases and genomic disorders (GDs) in 23 (3.1%) cases. We detected no significant differences in the overall diagnostic yield between COU sub-phenotypes, and pathogenic SNVs in several genes were associated to any of the three categories. Hence, although COU may appear phenotypically heterogeneous, COU phenotypes are likely to share common molecular bases. On the other hand, mutations in TNXB were more often identified in COU-NOS cases, demonstrating the diagnostic challenge in discriminating COU from hydronephrosis secondary to vesicoureteral reflux, particularly when diagnostic imaging is incomplete. Pathogenic SNVs in only six genes were found in more than one individual, supporting high genetic heterogeneity. Finally, convergence between data on SNVs and GDs suggest MYH11 as a dosage-sensitive gene possibly correlating with severity of COU. CONCLUSIONS: We established a genomic diagnosis in 10.0% of COU individuals. The findings underscore the urgent need to identify novel genetic susceptibility factors to COU to better define the natural history of the remaining 90% of cases without a molecular diagnosis.

Diagnosing Fabry nephropathy: the challenge of multiple kidney disease.

Fabry disease (FD) is an X-linked inherited lysosomal disorder due to a deficiency of the enzyme alpha-galactosidase A (α-gla) due to mutations in the GLA gene. These mutations result in plasma and lysosome accumulation of glycosphingolipids, leading to progressive organ damage and reduced life expectancy. Due to the availability of specific disease-modifying treatments, proper and timely diagnosis and therapy are essential to prevent irreversible complications. However, diagnosis of FD is often delayed because of the wide clinical heterogeneity of the disease and multiple organ involvement developing in variable temporal sequences. This observation is also valid for renal involvement, which may manifest with non-specific signs, such as proteinuria and chronic kidney disease, which are also common in many other nephropathies. Moreover, an additional confounding factor is the possibility of the coexistence of FD with other kidney disorders. Thus, suspecting and diagnosing FD nephropathy in patients with signs of kidney disease may be challenging for the clinical nephrologist. Herein, also through the presentation of a unique case of co-occurrence of autosomal dominant polycystic kidney disease and FD, we review the available literature on cases of coexistence of FD and other renal diseases and discuss the implications of these conditions. Moreover, we highlight the clinical, laboratory, and histological elements that may suggest clinical suspicion and address a proper diagnosis of Fabry nephropathy.

Role of Uric Acid in Vascular Remodeling: Cytoskeleton Changes and Migration in VSMCs.

The mechanisms by which hyperuricemia induces vascular dysfunction and contributes to cardiovascular disease are still debated. Phenotypic transition is a property of vascular smooth muscle cells (VSMCs) involved in organ damage. The aim of this study was to investigate the effects of uric acid (UA) on changes in the VSMC cytoskeleton, cell migration and the signals involved in these processes. MOVAS, a mouse VSMC line, was incubated with 6, 9 and 12 mg/dL of UA, angiotensin receptor blockers (ARBs), proteasome and MEK-inhibitors. Migration property was assessed in a micro-chemotaxis chamber and by phalloidin staining. Changes in cytoskeleton proteins (Smoothelin B (SMTB), alpha-Smooth Muscle Actin (αSMA), Smooth Muscle 22 Alpha (SM22α)), Atrogin-1 and MAPK activation were determined by Western blot, immunostaining and quantitative reverse transcription PCR. UA exposition modified SMT, αSMA and SM22α levels (p < 0.05) and significantly upregulated Atrogin-1 and MAPK activation. UA-treated VSMCs showed an increased migratory rate as compared to control cells (p < 0.001) and a re-arrangement of F-actin. Probenecid, proteasome inhibition and ARBs prevented the development of dysfunctional VSMC. This study shows, for the first time, that UA-induced cytoskeleton changes determine an increase in VSMC migratory rate, suggesting UA as a key player in vascular remodeling.

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.

Microplastics and Kidneys: An Update on the Evidence for Deposition of Plastic Microparticles in Human Organs, Tissues and Fluids and Renal Toxicity Concern.

Plastic pollution became a main challenge for human beings as demonstrated by the increasing dispersion of plastic waste into the environment. Microplastics (MPs) have become ubiquitous and humans are exposed daily to inhalation or ingestion of plastic microparticles. Recent studies performed using mainly spectroscopy or spectrometry-based techniques have shown astounding evidence for the presence of MPs in human tissues, organs and fluids. The placenta, meconium, breast milk, lung, intestine, liver, heart and cardiovascular system, blood, urine and cerebrovascular liquid are afflicted by MPs' presence and deposition. On the whole, obtained data underline a great heterogeneity among different tissue and organs of the polymers characterized and the microparticles' dimension, even if most of them seem to be below 50-100 µm. Evidence for the possible contribution of MPs in human diseases is still limited and this field of study in medicine is in an initial state. However, increasing studies on their toxicity in vitro and in vivo suggest worrying effects on human cells mainly mediated by oxidative stress, inflammation and fibrosis. Nephrological studies are insufficient and evidence for the presence of MPs in human kidneys is still lacking, but the little evidence present in the literature has demonstrated histological and functional alteration of kidneys in animal models and cytotoxicity through apoptosis, autophagy, oxidative stress and inflammation in kidney cells. Overall, the manuscript we report in this review recommends urgent further study to analyze potential correlations between kidney disease and MPs' exposure in human.

Evidence for charge-based mimicry in anti dsDNA antibody generation.

Mechanisms for the generation of anti-dsDNA autoantibodies are still not completely elucidated. One theory states that dsDNA interacts for mimicry with antibodies raised versus other antigens but molecular features for mimicry are unknown. Here we show that, at physiological acid-base balance, anti-Annexin A1 binds IgG2 dsDNA in a competitive and dose-dependent way with Annexin A1 and that the competition between the two molecules is null at pH 9. On the other hand, these findings also show that dsDNA and Annexin A1 interact with their respective antibodies on a strictly pH-dependent basis: in both cases, the binding was minimal at pH 4 and maximal at pH9-10. The anionic charge of dsDNA is mainly conferred by the numerous phosphatidic residues. The epitope binding site of Annexin A1 for anti-Annexin A1 IgG2 was here characterized as a string of 34 amino acids at the NH2 terminus, 10 of which are anionic. Circulating levels of anti-dsDNA and anti-Annexin A1 IgG2 antibodies were strongly correlated in patients with systemic lupus erythematosus (n 496) and lupus nephritis (n 425) stratified for age, sex, etc. These results show that dsDNA competes with Annexin A1 for the binding with anti-Annexin A1 IgG2 on a dose and charged mediated base, being able to display an inhibition up to 75%. This study provides the first demonstration that dsDNA may interact with antibodies raised versus other anionic molecules (anti-Annexin A1 IgG2) because of charge mimicry and this interaction may contribute to anti-dsDNA antibodies generation.

Renal Outcomes of Dialysis-Dependent Acute Kidney Injury in Noncritically Ill Patients: A Retrospective Study.

INTRODUCTION: Acute kidney injury (AKI) is a common complication among hospitalized patients, potentially affecting short- and long-term clinical outcomes. In this retrospective study, we evaluated renal outcomes in noncritically ill patients who required acute hemodialysis (HD) because of an AKI episode occurring during hospitalization. METHODS: Sixty-three hemodynamically stable patients with AKI undergoing acute intermittent HD were included. Kidney function was evaluated at baseline control (pre-AKI), at AKI diagnosis and during the follow-up. According to serum creatinine and the estimated glomerular filtration rate (eGFR), we defined three clinical conditions: renal recovery, different stages of acute kidney disease (AKD), and chronic kidney disease (CKD). RESULTS: Among the 63 patients evaluated, 34 patients (54%) had a history of CKD. Six patients (10%) presented early full renal recovery. HD treatment was stopped in 38 patients (60%), while 25 patients (40%) required maintenance HD. Dialysis-independent patients presented lower comorbidity and higher baseline eGFR and delta creatinine, compared to dialysis-dependent patients. Baseline CKD, previous AKI episodes, and parenchymal causes of AKI were associated with a significant risk of dialysis dependence. At 1-month control, 15 patients (39%) presented AKD stage 0, 6 patients (16%) AKD stage 1, and 17 patients (44%) AKD stage 2-3. At 3-month control, 29 out of 38 patients recovering from AKI (76%) presented CKD. AKD stage was significantly correlated with the risk of CKD development, which, resulted higher in patients with lower baseline eGFR. CONCLUSIONS: AKI might represent a risk factor for the development of chronic kidney damage, even in noncritically ill patients.

Second Wave Antibodies in Autoimmune Renal Diseases: The Case of Lupus Nephritis.

Clinical Trial registry name and registration number: Zeus study, NCT02403115.

Copy Number Variant Analysis and Genome-wide Association Study Identify Loci with Large Effect for Vesicoureteral Reflux.

BACKGROUND: Vesicoureteral reflux (VUR) is a common, familial genitourinary disorder, and a major cause of pediatric urinary tract infection (UTI) and kidney failure. The genetic basis of VUR is not well understood. METHODS: A diagnostic analysis sought rare, pathogenic copy number variant (CNV) disorders among 1737 patients with VUR. A GWAS was performed in 1395 patients and 5366 controls, of European ancestry. RESULTS: Altogether, 3% of VUR patients harbored an undiagnosed rare CNV disorder, such as the 1q21.1, 16p11.2, 22q11.21, and triple X syndromes ((OR, 3.12; 95% CI, 2.10 to 4.54; P=6.35×10-8) The GWAS identified three study-wide significant and five suggestive loci with large effects (ORs, 1.41-6.9), containing canonical developmental genes expressed in the developing urinary tract (WDPCP, OTX1, BMP5, VANGL1, and WNT5A). In particular, 3.3% of VUR patients were homozygous for an intronic variant in WDPCP (rs13013890; OR, 3.65; 95% CI, 2.39 to 5.56; P=1.86×10-9). This locus was associated with multiple genitourinary phenotypes in the UK Biobank and eMERGE studies. Analysis of Wnt5a mutant mice confirmed the role of Wnt5a signaling in bladder and ureteric morphogenesis. CONCLUSIONS: These data demonstrate the genetic heterogeneity of VUR. Altogether, 6% of patients with VUR harbored a rare CNV or a common variant genotype conferring an OR >3. Identification of these genetic risk factors has multiple implications for clinical care and for analysis of outcomes in VUR.

Proteomics and Extracellular Vesicles as Novel Biomarker Sources in Peritoneal Dialysis in Children.

Peritoneal dialysis (PD) represents the dialysis modality of choice for pediatric patients with end-stage kidney disease. Indeed, compared with hemodialysis (HD), it offers many advantages, including more flexibility, reduction of the risk of hospital-acquired infections, preservation of residual kidney function, and a better quality of life. However, despite these positive aspects, PD may be associated with several long-term complications that may impair both patient's general health and PD adequacy. In this view, chronic inflammation, caused by different factors, has a detrimental impact on the structure and function of the peritoneal membrane, leading to sclerosis and consequent PD failure both in adults and children. Although several studies investigated the complex pathogenic pathways underlying peritoneal membrane alterations, these processes remain still to explore. Understanding these mechanisms may provide novel approaches to improve the clinical outcome of pediatric PD patients through the identification of subjects at high risk of complications and the implementation of personalized interventions. In this review, we discuss the main experimental and clinical experiences exploring the potentiality of the proteomic analysis of peritoneal fluids and extracellular vesicles as a source of novel biomarkers in pediatric peritoneal dialysis.

Serum IgG2 antibody multicomposition in systemic lupus erythematosus and lupus nephritis (Part 1): cross-sectional analysis.

OBJECTIVES: Serum anti-dsDNA and anti-nucleosome IgGs have been proposed as signatures for SLE and LN in limited numbers of patients. We sought to show higher sensitivity and specificity of the same antibodies with the IgG2 isotype and included IgG2 antibodies vs specific intracellular antigens in the analysis. METHODS: A total of 1052 SLE patients with (n = 479) and without (n = 573) LN, recruited at different times from the beginning of symptoms, were included in the study. Patients with primary APS (PAPS, n = 24), RA (RA, n = 24) and UCTD (UCTD, n = 96) were analysed for comparison. Anti-nucleosome (dsDNA, Histone2A, Histone3), anti-intracellular antigens (ENO1), anti-annexin A1 and anti-C1q IgG2 were determined by non-commercial techniques. RESULTS: The presence in the serum of the IgG2 panel was highly discriminatory for SLE/LN vs healthy subjects. Serum levels of anti-dsDNA and anti-C1q IgG2 were more sensitive than those of IgGs (Farr radioimmunoassay/commercial assays) in identifying SLE patients at low-medium increments. Of more importance, serum positivity for anti-ENO1 and anti-H2A IgG2 discriminated between LN and SLE (ROC T0-12 months), and high levels at T0-1 month were detected in 63% and 67%, respectively, of LN, vs 3% and 3%, respectively, of SLE patients; serum positivity for each of these was correlated with high SLEDAI values. Minor differences existed between LN/SLE and the other rheumatologic conditions. CONCLUSION: Nephritogenic IgG2 antibodies represent a specific signature of SLE/LN, with a few overlaps with other rheumatologic conditions. High levels of anti-ENO1 and anti-H2A IgG2 correlated with SLE activity indexes and were discriminatory between SLE patients limited to the renal complication and other SLE patients. TRIAL REGISTRATION: The Zeus study was registered at https://clinicaltrials.gov, NCT02403115.

Serum IgG2 antibody multi-composition in systemic lupus erythematosus and in lupus nephritis (Part 2): prospective study.

OBJECTIVES: Circulating anti-ENO1 and anti-H2A IgG2 have been identified as specific signatures of LN in a cross-over approach. We sought to show whether the same antibodies identify selected population of patients with LN with potentially different clinical outcomes. METHODS: Here we report the prospective analysis over 36 months of circulating IgG2 levels in patients with newly diagnosed LN (n=91) and SLE (n=31) and in other patients with SLE recruited within 2 years from diagnosis (n=99). Anti-podocyte (ENO1), anti-nucleosome (DNA, histone 2 A, histone 3) and anti-circulating proteins (C1q, AnnexinA1-ANXA1) IgG2 antibodies were determined by home-made techniques. RESULTS: LN patients were the main focus of the study. Anti-ENO1, anti-H2A and anti-ANXA1 IgG2 decreased in parallel to proteinuria and normalized within 12 months in the majority of patients while anti-dsDNA IgG2 remained high over the 36 months. Anti-ENO1 and anti-H2A had the highest association with proteinuria (Heat Map) and identified the highest number of patients with high proteinuria (68% and 71% respectively) and/or with reduced estimated glomerula filtration rate (eGFR) (58% for both antibodies) compared with 23% and 17% of anti-dsDNA (agreement analysis). Anti-ENO1 positive LN patients had higher proteinuria than negative patients at T0 and presented the maximal decrement within 12 months. CONCLUSIONS: Anti-ENO1, anti-H2A and anti-ANXA1 antibodies were associated with high proteinuria in LN patients and Anti-ENO1 also presented the maximal reduction within 12 months that paralleled the decrease of proteinuria. Anti-dsDNA were not associated with renal outcome parameters. New IgG2 antibody signatures should be utilized as tracers of personalized therapies in LN. TRIAL REGISTRATION: The Zeus study was registered at https://clinicaltrials.gov (study number: NCT02403115).

Volume Balance in Chronic Kidney Disease: Evaluation Methodologies and Innovation Opportunities.

BACKGROUND: Patients affected by chronic kidney disease are at a risk of cardiovascular morbidity and mortality. Body fluids unbalance is one of the main characteristics of this condition, as fluid overload is highly prevalent in patients affected by the cardiorenal syndrome. SUMMARY: We describe the state of the art and new insights into body volume evaluation. The mechanisms behind fluid balance are often complex, mainly because of the interplay of multiple regulatory systems. Consequently, its management may be challenging in clinical practice and even more so out-of-hospital. Availability of novel technologies offer new opportunities to improve the quality of care and patients' outcome. Development and validation of new technologies could provide new tools to reduce costs for the healthcare system, promote personalized medicine, and boost home care. Due to the current COVID-19 pandemic, a proper monitoring of chronic patients suffering from fluid unbalances is extremely relevant. Key Message: We discuss the main mechanisms responsible for fluid overload in different clinical contexts, including hemodialysis, peritoneal dialysis, and heart failure, emphasizing the potential impact provided by the implementation of the new technologies.

Cellular Senescence Is Associated with Faster Progression of Focal Segmental Glomerulosclerosis.

BACKGROUND: A current, albeit unproven, hypothesis is that an acceleration of cellular senescence is involved in impaired renal repair and progression of glomerular diseases. Focal segmental glomerulosclerosis (FSGS) is a glomerular disease with a substantial risk for progression to ESRD. However, if and to what extent cell senescence predicts a negative outcome in FSGS is still unknown. METHODS: The hypothesis that cell senescence represents a proximate mechanism by which the kidney is damaged in FSGS (NOS phenotype) was investigated in 26 consecutive kidney biopsies from adult FSGS cases (eGFR 72 ± 4 mL/min, proteinuria 2.3 ± 0.6 g/day) who were incident for 2 years in a Northern Italian nephrology center and had a 6-year clinical follow-up. RESULTS: Cell senescence (p16INK4A, SA-ß-galactosidase [SA-ß-Gal]) was upregulated by ∼3- to 4-fold in both glomerular and tubular cells in kidney biopsies of FSGS as compared to age-matched controls (p < 0.05-0.01). Tubular SA-ß-Gal correlated with proteinuria and glomerulosclerosis, while only as a trend, tubular p16INK4A was directly associated with interstitial fibrosis. At univariate analysis, basal eGFR, proteinuria, and tubular expression of SA-ß-Gal and p16INK4A were significantly directly related to the annual loss of eGFR. No correlation was observed between glomerular p16INK4A and eGFR loss. However, at multivariate analysis, eGFR, proteinuria, and tubular p16INK4A, but not SA-ß-Gal, contributed significantly to the prediction of eGFR loss. CONCLUSIONS: The results indicate that an elevated cell senescence rate, expressed by an upregulation of p16INK4A in tubules at the time of initial biopsy, represents an independent predictor of progression to ESRD in adult patients with FSGS.

Muscle protein turnover and low-protein diets in patients with chronic kidney disease.

Adaptation to a low-protein diet (LPD) involves a reduction in the rate of amino acid (AA) flux and oxidation, leading to more efficient use of dietary AA and reduced ureagenesis. Of note, the concept of 'adaptation' to low-protein intakes has been separated from the concept of 'accommodation', the latter term implying a decrease in protein synthesis, with development of wasting, when dietary protein intake becomes inadequate, i.e. beyond the limits of the adaptive mechanisms. Acidosis, insulin resistance and inflammation are recognized mechanisms that can increase protein degradation and can impair the ability to activate an adaptive response when an LPD is prescribed in a chronic kidney disease (CKD) patient. Current evidence shows that, in the short term, clinically stable patients with CKD Stages 3-5 can efficiently adapt their muscle protein turnover to an LPD containing 0.55-0.6 g protein/kg or a supplemented very-low-protein diet (VLPD) by decreasing muscle protein degradation and increasing the efficiency of muscle protein turnover. Recent long-term randomized clinical trials on supplemented VLPDs in patients with CKD have shown a very good safety profile, suggesting that observations shown by short-term studies on muscle protein turnover can be extrapolated to the long-term period.

Evaluation of Hypertension, Proteinuria, and Abnormalities of Body Weight in Italian Adolescents Participating in the World Kidney Days.

INTRODUCTION: World Kidney Day (WKD) was promoted by the Italian Kidney Foundation and the Italian Society of Nephrology for raising awareness, detection, prevention, and treatment of kidney diseases. The Italian WKD focused on the "School Project" by screening students attending the fifth year of high school. The main goal of the "School Project" was to assess in healthy adolescents the presence of hypertension (HTN) and proteinuria; as well as to evaluate potential interrelations between overweight, obesity (both measured with different anthropometric methods), blood pressure (BP) levels, and proteinuria. The ancillary goal was to have an estimate of awareness on some nephrology topics. METHODS: The study population consisted of 17- to 19-year-old students. HTN was defined as systolic BP (SBP) ≥140 mm Hg and/or diastolic BP (DBP) ≥90 mm Hg. Isolated systolic hypertension (ISH) was defined as SBP ≥140 mm Hg and DBP <90 mm Hg; isolated diastolic hypertension as SBP <140 mm Hg and DBP ≥90 mm Hg; systolic and diastolic hypertension as SBP ≥140 mm Hg and DBP ≥90 mm Hg; pre-hypertension as SBP >120 mm Hg but <140 mm Hg or DBP >80 mm Hg but <90 mm Hg; and optimal BP as SBP ≤120 mm Hg and DBP ≤80 mm Hg. Urine tests were performed with a dipstick; the subjects were regarded as proteinuric when the urine dipstick was positive (proteinuria ≥30 mg/dL). Body weight, height, and waist circumference (WC) were measured; body mass index (BMI), waist-to-height ratio (WHtR), and conicity index (Ci) were calculated. According to the BMI, the following classifications were adopted: underweight (<18.5 kg/m2), normal weight (18.5-24.9 kg/m2), overweight (25-29.9 kg/m2), class-I obesity (30-34.9 kg/m2), class-II obesity (35-39.9 kg/m2), class-III obesity (≥40 kg/m2). RESULTS: Data from 12,125 students (45.6% males) were evaluated. HTN was found in 1,349 participants (11.1%; 61.1% male), and ISH was present in 7.4%. Overweight (24.1%) and class-I (6%), -II (3.6%), and -III (1%) obesity were present in hypertensive participants. Compared to participants with normal BP, hypertensive participants had a higher BMI (p < 0.001), WC (p < 0.001), and WHtR (p < 0.001); whereas the Ci was not different (p = 0.527). Multivariate linear regression analysis showed that both WC and BMI were predictors of abnormal SBP and DBP (p < 0.001) both in males and females. Proteinuria was present in 14.8, 13.8, 14.7, and 14.7% of all normal weight, overweight, obese, and all subjects, respectively. In addition, no association was found between body weight, proteinuria, and BP. CONCLUSION: This study shows that overweight and obesity were significantly associated to HTN in Italian adolescents. BMI and WC were predictors of SBP and DBP. The occurrence of proteinuria was quite similar to that of HTN, but it was not associated with anthropometric indicators or HTN.