Mind the gap in kidney care: translating what we know into what we do.

Historically, it takes an average of 17 years to move new treatments from clinical evidence to daily practice. Given the highly effective treatments now available to prevent or delay kidney disease onset and progression, this is far too long. The time is now to narrow the gap between what we know and what we do. Clear guidelines exist for the prevention and management of common risk factors for kidney disease, such as hypertension and diabetes, but only a fraction of people with these conditions worldwide are diagnosed, and even fewer are treated to target. Similarly, the vast majority of people living with kidney disease are unaware of their condition, because in the early stages it is often silent. Even among patients who have been diagnosed, many do not receive appropriate treatment for kidney disease. Considering the serious consequences of kidney disease progression, kidney failure, or death, it is imperative that treatments are initiated early and appropriately. Opportunities to diagnose and treat kidney disease early must be maximized beginning at the primary care level. Many systematic barriers exist, ranging from patient to clinician to health systems to societal factors. To preserve and improve kidney health for everyone everywhere, each of these barriers must be acknowledged so that sustainable solutions are developed and implemented without further delay.

Mind the gap in kidney care: Translating what we know into what we do.

Historically, it takes an average of 17 years to move new treatments from clinical evidence to daily practice. Given the highly effective treatments now available to prevent or delay kidney disease onset and progression, this is far too long. The time is now to narrow the gap between what we know and what we do. Clear guidelines exist for the prevention and management of common risk factors for kidney disease, such as hypertension and diabetes, but only a fraction of people with these conditions worldwide are diagnosed, and even fewer are treated to target. Similarly, the vast majority of people living with kidney disease are unaware of their condition, because in the early stages it is often silent. Even among patients who have been diagnosed, many do not receive appropriate treatment for kidney disease. Considering the serious consequences of kidney disease progression, kidney failure, or death, it is imperative that treatments are initiated early and appropriately. Opportunities to diagnose and treat kidney disease early must be maximized beginning at the primary care level. Many systematic barriers exist, ranging from patient to clinician to health systems to societal factors. To preserve and improve kidney health for everyone everywhere, each of these barriers must be acknowledged so that sustainable solutions are developed and implemented without further delay.

Effect of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers on cardiovascular outcomes in dialysis patients: a systematic review and meta-analysis.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs) are recommended by guidelines as first-line antihypertensive therapies in the general population or in patients with earlier stages of kidney disease. However, the cardioprotective benefit of these agents among patients on dialysis remains uncertain. METHODS: We searched the MEDLINE, PubMed and Cochrane databases from inception through February 2022 to identify randomized controlled trials (RCTs) comparing the efficacy of ACEIs/ARBs relative to placebo or no add-on treatment in patients receiving dialysis. RCTs were eligible if they assessed fatal or non-fatal cardiovascular events as a primary efficacy endpoint. RESULTS: We identified five RCTs involving 1582 dialysis patients. Compared with placebo or no add-on treatment, the use of ACEIs/ARBs was not associated with a significantly lower risk of cardiovascular events {risk ratio [RR] 0.79 [95% confidence interval (CI) 0.57-1.11]}. Furthermore, there was no benefit in cardiovascular mortality [RR 0.82 (95% CI 0.59-1.14)] and all-cause mortality [RR 0.86 (95% CI 0.64-1.15)]. These results were consistent when the included RCTs were stratified by subgroups, including hypertension, ethnicity, sample size, duration of follow-up and quality. CONCLUSION: The present meta-analysis showed that among patients on dialysis, the use of ACEIs/ARBs is not associated with a significantly lower risk of cardiovascular events and all-cause mortality as compared with placebo or no add-on treatment.

Myasthenia gravis genome-wide association study implicates AGRN as a risk locus.

BACKGROUND: Myasthenia gravis (MG) is a rare autoimmune disorder affecting the neuromuscular junction (NMJ). Here, we investigate the genetic architecture of MG via a genome-wide association study (GWAS) of the largest MG data set analysed to date. METHODS: We performed GWAS meta-analysis integrating three different data sets (total of 1401 cases and 3508 controls). We carried out human leucocyte antigen (HLA) fine-mapping, gene-based and tissue enrichment analyses and investigated genetic correlation with 13 other autoimmune disorders as well as pleiotropy across MG and correlated disorders. RESULTS: We confirmed the previously reported MG association with TNFRSF11A (rs4369774; p=1.09×10-13, OR=1.4). Furthermore, gene-based analysis revealed AGRN as a novel MG susceptibility gene. HLA fine-mapping pointed to two independent MG loci: HLA-DRB1 and HLA-B. MG onset-specific analysis reveals differences in the genetic architecture of early-onset MG (EOMG) versus late-onset MG (LOMG). Furthermore, we find MG to be genetically correlated with type 1 diabetes (T1D), rheumatoid arthritis (RA), late-onset vitiligo and autoimmune thyroid disease (ATD). Cross-disorder meta-analysis reveals multiple risk loci that appear pleiotropic across MG and correlated disorders. DISCUSSION: Our gene-based analysis identifies AGRN as a novel MG susceptibility gene, implicating for the first time a locus encoding a protein (agrin) that is directly relevant to NMJ activation. Mutations in AGRN have been found to underlie congenital myasthenic syndrome. Our results are also consistent with previous studies highlighting the role of HLA and TNFRSF11A in MG aetiology and the different risk genes in EOMG versus LOMG. Finally, we uncover the genetic correlation of MG with T1D, RA, ATD and late-onset vitiligo, pointing to shared underlying genetic mechanisms.

Epidemiology of Hypertension among Patients on Peritoneal Dialysis Using Standardized Office and Ambulatory Blood Pressure Recordings.

INTRODUCTION: Prior studies conducted in peritoneal dialysis (PD) patients in the late 1990s provided considerably variable estimates of the prevalence and control of hypertension. The present study aimed to investigate the current state of hypertension management in this high-risk population. METHODS: In 140 stable PD patients, we performed standardized automated office blood pressure (BP) measurements and 24-h ambulatory BP monitoring (ABPM) using the Mobil-O-Graph device (IEM, Germany). Office and ambulatory hypertension was diagnosed in patients with office BP ≥140/90 mm Hg and 24-h BP ≥130/80 mm Hg, respectively. Patients treated with ≥1 BP-lowering medications were also classified as hypertensives. RESULTS: The prevalence of office and ambulatory hypertension was 92.9% and 95%, respectively. In all, 92.1% of patients were being treated with an average of 2.4 BP-lowering medications daily. Adequate BP control was achieved in 52.3% and 38.3% of hypertensives by office BP and ABPM, respectively. The agreement between these 2 techniques in the identification of patients with BP levels above the diagnostic thresholds of hypertension was moderate (k-statistic: 0.524). In all, 5% of patients were normotensives with both techniques, 31.4% had controlled hypertension, 5% had white-coat hypertension, 19.3% had masked hypertension, and 39.3% had sustained hypertension. Isolated nocturnal hypertension was detected in 23.6% of patients, whereas no patient had isolated daytime hypertension. CONCLUSION: Among PD patients, hypertension is highly prevalent and remains often inadequately controlled. The use of ABPM enables the better classification of severity of hypertension and identification of isolated nocturnal hypertension, which is a common BP phenotype in the PD population.

The Role of Nucleases Cleaving TLR3, TLR7/8 and TLR9 Ligands, Dicer RNase and miRNA/piRNA Proteins in Functional Adaptation to the Immune Escape and Xenophagy of Prostate Cancer Tissue.

The prototypic sensors for the induction of innate and adaptive immune responses are the Toll-like receptors (TLRs). Unusually high expression of TLRs in prostate carcinoma (PC), associated with less differentiated, more aggressive and more propagating forms of PC, changed the previous paradigm about the role of TLRs strictly in immune defense system. Our data reveal an entirely novel role of nucleic acids-sensing Toll-like receptors (NA-TLRs) in functional adaptation of malignant cells for supply and digestion of surrounding metabolic substrates from dead cells as specific mechanism of cancer cells survival, by corresponding ligands accelerated degradation and purine/pyrimidine salvage pathway. The spectrophotometric measurement protocols used for the determination of the activity of RNases and DNase II have been optimized in our laboratory as well as the enzyme-linked immunosorbent method for the determination of NF-κB p65 in prostate tissue samples. The protocols used to determine Dicer RNase, AGO2, TARBP2 and PIWIL4 were based on enzyme-linked immunosorbent assay. The amount of pre-existing acid-soluble oligonucleotides was measured and expressed as coefficient of absorbance. The activities of acid DNase II and RNase T2, and the activities of nucleases cleaving TLR3, TLR7/8 and TLR9 ligands (Poly I:C, poly U and unmethylated CpG), increased several times in PC, compared to the corresponding tumor adjacent and control tissue, exerting very high sensitivity and specificity of above 90%. Consequently higher levels of hypoxanthine and NF-κB p65 were reported in PC, whereas the opposite results were observed for miRNA biogenesis enzyme (Dicer RNase), miRNA processing protein (TARB2), miRNA-induced silencing complex protein (Argonaute-AGO) and PIWI-interacting RNAs silence transposon. Considering the crucial role of purine and pyrimidine nucleotides as energy carriers, subunits of nucleic acids and nucleotide cofactors, future explorations will be aimed to design novel anti-cancer immune strategies based on a specific acid endolysosomal nuclease inhibition.

Sleep Apnea as a Cardiorenal Risk Factor in CKD and Renal Transplant Patients.

BACKGROUND: Chronic kidney disease (CKD) is a public health priority of increasing concern worldwide. Sleep apnea (SA) of moderate-to-severe degree has a 3-9% prevalence in women and 10-17% in men in the general population. SUMMARY: In CKD patients, the prevalence of SA parallels the decline of the GFR being 27% in CKD patients with a GFR of >60 mL/min/1.73 m2 and 57% in patients with end-stage kidney disease (ESKD). In the early CKD stages, fluid overload is probably the sole risk factor for SA in this population. At more severe CKD stages, disturbed central and peripheral chemosensitivity and the accumulation of uremic toxins might contribute to SA. Still, there is no direct evidence supporting this hypothesis in human studies. Observational studies coherently show that SA is a risk factor for CKD incidence and CKD progression as well as for cardiovascular disease and death in this population. However, there is no randomized clinical trial testing continuous positive airway pressure or other interventions documenting that attenuation of SA may have a favorable effect on renal and cardiovascular outcomes in CKD and ESKD patients. However, most likely, the causal nature of the association between SA and cardiorenal outcomes remains unproven. Renal transplantation is the most effective treatment of SA in patients with ESKD, but this disturbance re-emerges on long-term observation in this population. However, after renal transplantation, SA does not seem to be a predictor of adverse health outcomes.

Be careful with ecological associations.

Ecological studies are observational studies commonly used in public health research. The main characteristic of this study design is that the statistical analysis is based on pooled (i.e., aggregated) rather than on individual data. Thus, patient-level information such as age, gender, income and disease condition are not considered as individual characteristics but as mean values or frequencies, calculated at country or community level. Ecological studies can be used to compare the aggregated prevalence and incidence data of a given condition across different geographical areas, to assess time-related trends of the frequency of a pre-defined disease/condition, to identify factors explaining changes in health indicators over time in specific populations, to discriminate genetic from environmental causes of geographical variation in disease, or to investigate the relationship between a population-level exposure and a specific disease or condition. The major pitfall in ecological studies is the ecological fallacy, a bias which occurs when conclusions about individuals are erroneously deduced from results about the group to which those individuals belong. In this paper, by using a series of examples, we provide a general explanation of the ecological studies and provide some useful elements to recognize or suspect ecological fallacy in this type of studies.

The hazard ratio as a measure of effect in clinical trials of elderly populations: common pitfalls and misconceptions.

The hazard ratio is a measure of effect which is of paramount importance in etiological research, that is in studies aimed at assessing the strength of the causal relationship between a given treatment/exposure and a certain outcome. Despite the widespread use of the hazard ratio as a measure of effect in scientific reports and articles, the interpretation of this index is often accompanied by some misconceptions which can jeopardize the critical appraisal of randomized clinical trials (RCTs) and observational studies as well. Herein, using a series of examples derived from RCTs in the elderly subjects, we address major pitfalls regarding the interpretation of the hazard ratio in geriatric research.

Sample size calculation of clinical trials in geriatric medicine.

A preliminary step when planning a randomized clinical trial (RCT) is the sample size calculation. This is the determination of the optimal number of patients which ensures an adequate power to the study to detect as statistically significant a certain between-arms difference, if any, in the frequency/magnitude of a specific endpoint. The sample size calculation is performed by specific calculators requiring as input variables the expected effect size, the alpha error (α), the beta error (ß) and the allocation ratio, this latter being the ratio between the number of participants allocated to the arms of a RCT. Herein, we provide a series of examples of sample size calculation in the context of superiority RCTs in elderly.

Statistical methods to assess the prognostic value of risk prediction rules in clinical research.

Prognosis aims at estimating the future course of a given disease in probabilistic terms. As in diagnosis, where clinicians are interested in knowing the accuracy of a new test to identify patients affected by a given disease, in prognosis they wish to accurately identify patients at risk of a future event conditional to one or more prognostic factors. Thus, accurate risk predictions play a primary role in all fields of clinical medicine and in geriatrics as well because they can help clinicians to tailor the intensity of a treatment and to schedule clinical surveillance according to the risk of the concerned patient. Statistical methods able to evaluate the prognostic accuracy of a risk score demand the assessment of discrimination (the Harrell's C-index), calibration (Hosmer-May test) and risk reclassification abilities (IDI, an index of risk reclassification) of the same risk prediction rule whereas, in spite of the popular belief that traditional statistical techniques providing relative measures of effect (such as the hazard ratio derived by Cox regression analysis or the odds ratio obtained by logistic regression analysis) could be per se enough to assess the prognostic value of a biomarker or of a risk score. In this paper we provide a brief theoretical background of each statistical test and a practical approach to the issue. For didactic purposes, in the paper we also provide a dataset (n = 40) to allow the reader to train in the application of the proposed statistical methods.

Prognostic Factors of Fatal and Nonfatal Cardiovascular Events in Patients With Type 2 Diabetes: The Role of Renal Function Biomarkers.

In this study, 158 patients with different degrees of renal function were followed for 7 years to assess the prognostic value of various risk factors, including carotid intima-media thickness (cIMT) and biomarkers of renal function, for incident cardiovascular morbidity and mortality in patients with type 2 diabetes. The investigators found that estimated glomerular filtration rate, albuminuria, and history of cardiovascular disease (CVD) can be used for prognosis of CVD, whereas cIMT adds little to the accuracy of this prediction.

Ferritin modifies the relationship between inflammation and arterial stiffness in hypertensive patients with different glucose tolerance.

BACKGROUND: Ferritin, a crucial element for iron homeostasis, is associated with chronic diseases characterized by subclinical inflammation such as essential arterial hypertension and type 2 diabetes mellitus (T2DM), showing a prognostic value in different clinical settings. We investigated whether ferritin is associated with arterial stiffness (AS), an early indicator of atherosclerosis, and if it could act as effect modifier on the relationship between inflammation and AS in hypertensive patients with different glucose tolerance. METHODS: We enrolled 462 newly diagnosed untreated hypertensive (HT) patients. All subjects underwent an oral glucose tolerance test. Insulin sensitivity was assessed by MATSUDA index and ferritin levels were estimated by immunoradiometric assay. AS was defined by carotid-femoral pulse wave velocity (PWV). RESULTS: Out of 462 patients, 271 showed normal glucose tolerance (HT/NGT), 146 impaired glucose tolerance (HT/IGT) and 45 were diabetic (HT/T2DM). Iron levels significantly decreased and transferrin and ferritin significantly increased from the first to the third group. PWV values were significantly higher in HT/IGT and HT/T2DM patients. PWV was related directly with ferritin, high sensitivity C reactive protein (hs-CRP), transferrin, and inversely with MATSUDA index. Ferritin resulted the strongest determinant of PWV explaining a 14.9% of its variation; moreover it was a strong modifier of the relationship between hs-CRP and PWV. The estimated augmentation in PWV portended by a fixed increase in hs-CRP, was higher across increasing values of ferritin. CONCLUSION: Ferritin represents an independent risk factor of arterial stiffness in our study population and a strong effect modifier on the relationship between inflammation and PWV. However, further studies are needed to fully elucidate the potential role of this biomarker in human atherosclerosis.

10-year-long survival in a PD patient with severe calcifying encapsulating peritoneal sclerosis treated with tamoxifen: a case-report.

BACKGROUND: Encapsulating-peritoneal-sclerosis (EPS) is a rare, but serious and life-threatening complication of peritoneal dialysis (PD). Treatment of EPS consists of discontinuation of PD and maintenance of nutritional status, whereas the role of corticosteroids, tamoxifen and other immunosuppresive agents is not yet fully elucidated. CASE-PRESENTATION: We report the case of a 28-year-old patient, who developed a severe form of calcifying EPS after a 6-year-long therapy with automated PD. The clinical presentation was severe with repeated episodes of total bowel obstruction, weight loss and malnutrition that mandated his prolonged hospitalization. Initial treatment included corticosteroids and tamoxifen (20 mg/day) with a clinically meaningful improvement in gastrointestinal function and nutritional status over the first 6-12 months. Corticosteroids were discontinued at 18 months, but owing to persistence of calcifying lesions and peritoneal thickening in repeated computed-tomography (CT) scans, tamoxifen remained unmodified at a low-dose of 20 mg/day for a 10-year-long period. During follow-up, the patient remained symptoms-free in an excellent clinical condition and the CT findings were unchanged. CONCLUSIONS: Long-term administration of tamoxifen was not accompanied by any drug-related adverse effects and potentially exerted a beneficial action on down-regulation of inflammatory and fibrotic processes and improvement of gastrointestinal function, nutritional status and overall health-related quality of life.

The Association of dp-ucMGP with Cardiovascular Morbidity and Decreased Renal Function in Diabetic Chronic Kidney Disease.

We aimed to investigate the possible association of the inactive, dephosphorylated, uncarboxylated matrix Gla protein (dp-ucMGP) with oxidized low-density lipoprotein (ox-LDL) and all-cause/cardiovascular (CV) mortality and renal function in diabetic chronic kidney disease (CKD). Ox-LDL and dp-ucMGP were determined in 66 diabetic CKD patients. All patients were prospectively followed for seven years, or until the occurrence of death, or a composite renal outcome of 30% estimated glomerular filtration rate (eGFR) reduction or progression to end-stage renal disease (ESRD) requiring dialysis occurred. Secondary outcomes were the occurrence of CV events. Kaplan-Meier curves showed that patients with plasma dp-ucMGP levels above the median (≥656 pM) had a significantly higher risk for all study endpoints. After adjustment for several well-known cofounders, multivariate Cox analysis showed that high plasma dp-ucMGP levels were associated with all-cause mortality (Hazard ratio-HR = 2.63, 95% Confidence Interval-CI = 1.17-5.94, p = 0.02), CV mortality (HR = 2.82, 95% CI = 1.07-7.49, p = 0.037) and progression of CKD (HR = 4.02, 95% CI = 1.20-13.46, p = 0.024). Circulating dp-ucMGP is associated with mortality and decreased renal function in diabetic CKD.

Is oxidative stress an issue in peritoneal dialysis?

During the last two decades, oxidative stress (OS) has emerged as a novel risk factor for a variety of adverse events, including atherosclerosis and mortality in chronic kidney disease (CKD) patients. Increased OS occurs even in early stages of the disease, progresses with deterioration of renal function and is further aggravated by hemodialysis (HD), due to the bioincompatibility of the method. Compared to HD, peritoneal dialysis (PD) is a more biocompatible dialysis modality, characterized by a significantly reduced, but still high, OS status. The culprit for OS in PD is mainly the composition of PD solutions (low pH, lactate buffer, increased osmolarity and high glucose concentration). After heat sterilization of PD solutions, formation of glucose degradation products (GDPs) and advanced glycation end-products (AGEs) trigger inflammation and enhance OS. Chronic exposure of the peritoneum to this toxic, hyperglycemic environment leads to OS-derived morphologic damage of peritoneal cells, loss of ultrafiltration capacity and decreased technique survival. Moreover, OS is linked with peritonitis, loss of residual renal function, inflammation, atherosclerosis, cardiovascular (CV) disease, and increased mortality. To ameliorate OS status in PD, a multitargeted approach is necessary that includes use of neutral pH, low GDP, low lactate and iso-ismolar PD solutions, strict glycemic control, optimal volume management and, probably supplementation with antioxidants, N-acetylcysteine being the most promising among them.

Oxidative stress in hemodialysis: Causative mechanisms, clinical implications, and possible therapeutic interventions.

Oxidative stress (OS) is the result of prooxidant molecules overwhelming the antioxidant defense mechanisms. Hemodialysis (HD) constitutes a state of elevated inflammation and OS, due to loss of antioxidants during dialysis and activation of white blood cells triggering production of reactive oxygen species. Dialysis vintage, dialysis methods, and type and condition of vascular access, biocompatibility of dialyzer membrane and dialysate, iron administration, and anemia all can play a role in aggravating OS, which in turn has been associated with increased morbidity and mortality. Oral or intravenous administration of antioxidants may detoxify the oxidative molecules and at least in part repair OS-mediated tissue damage. Lifestyle interventions and optimization of a highly biocompatible HD procedure might ameliorate OS development in dialysis.

Carotid intima-media thickness is an independent predictor of all-cause mortality and cardiovascular morbidity in patients with diabetes mellitus type 2 and chronic kidney disease.

BACKGROUND: Intima-Media-Thickness of the carotid artery wall (cIMT) is a strong predictor of cardiovascular (CV) disease. The aim of this study was to investigate the significance of cIMT as an independent prognostic factor for CV morbidity and mortality in patients with chronic kidney disease (CKD) and diabetes mellitus type 2 (DM2). METHODS: The study included 142 diabetic patients in different stages of CKD. Patients were categorized into two groups according to low (≤0.86 mm) or high cIMT (>0.86 mm), respectively. CV events and death from all causes were registered during a seven-year follow-up. RESULTS: Mean age, BMI and duration of diabetes were 68 years (range: 45-90), >30 kg/m2 and 15 years (range: 5-40), respectively. Patients with increased cIMT were older, suffered from a lower estimated glomerular filtration rate (eGFR), peripheral atherosclerosis and plaque presence in either carotid artery. Increased BMI (beta= -0.29, p = .01), lower eGFR (beta = 0.353, p = .003) and male gender (beta= -0.339, p = .005) were found to predict increased cIMT. Predictors of all-cause mortality in Cox proportional hazard models were low eGFR and high cIMT with HR = 0.96 (CI = 0.94-0.98), p < .001 and HR = 2.9 (CI = 1.03-7.99), p = .04, respectively. The risk of future CV event was determined by albuminuria and cIMT with HR = 1 (CI = 1.0-1.0), p < .001 and HR = 2.04 (CI = 1.1-3.78), p = .02, respectively. Patients with high cIMT presented significantly higher all-cause mortality and a new CV event (p = .005/p = .018, respectively). CONCLUSIONS: cIMT is a strong and independent predictor of CV morbidity and mortality, and should be considered a valuable tool for the stratification of CV risk in patients with CKD and DM2.

Oxidative Stress in the Pathogenesis and Evolution of Chronic Kidney Disease: Untangling Ariadne's Thread.

Amplification of oxidative stress is present since the early stages of chronic kidney disease (CKD), holding a key position in the pathogenesis of renal failure. Induction of renal pro-oxidant enzymes with excess generation of reactive oxygen species (ROS) and accumulation of dityrosine-containing protein products produced during oxidative stress (advanced oxidation protein products-AOPPs) have been directly linked to podocyte damage, proteinuria, and the development of focal segmental glomerulosclerosis (FSGS) as well as tubulointerstitial fibrosis. Vascular oxidative stress is considered to play a critical role in CKD progression, and ROS are potential mediators of the impaired myogenic responses of afferent renal arterioles in CKD and impaired renal autoregulation. Both oxidative stress and inflammation are CKD hallmarks. Oxidative stress promotes inflammation via formation of proinflammatory oxidized lipids or AOPPs, whereas activation of nuclear factor κB transcription factor in the pro-oxidant milieu promotes the expression of proinflammatory cytokines and recruitment of proinflammatory cells. Accumulating evidence implicates oxidative stress in various clinical models of CKD, including diabetic nephropathy, IgA nephropathy, polycystic kidney disease as well as the cardiorenal syndrome. The scope of this review is to tackle the issue of oxidative stress in CKD in a holistic manner so as to provide a future framework for potential interventions.